EP1558232A2 - Treating obesity with selective androgen receptor modulators - Google Patents

Treating obesity with selective androgen receptor modulators

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Publication number
EP1558232A2
EP1558232A2 EP03777596A EP03777596A EP1558232A2 EP 1558232 A2 EP1558232 A2 EP 1558232A2 EP 03777596 A EP03777596 A EP 03777596A EP 03777596 A EP03777596 A EP 03777596A EP 1558232 A2 EP1558232 A2 EP 1558232A2
Authority
EP
European Patent Office
Prior art keywords
nhcor
conhr
cor
snr
represented
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03777596A
Other languages
German (de)
French (fr)
Other versions
EP1558232A4 (en
Inventor
James T. Dalton
Duane D. Miller
Mitchell S. Steiner
Karen A. Veverka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Oncternal Therapeutics Inc
Original Assignee
GTx Inc
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Filing date
Publication date
Application filed by GTx Inc filed Critical GTx Inc
Publication of EP1558232A2 publication Critical patent/EP1558232A2/en
Publication of EP1558232A4 publication Critical patent/EP1558232A4/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to the prevention and treatment of obesity. More particularly, this invention relates to a method of a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat firee body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes mellitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin; comprising administering a therapeutically effective amount of a selective androgen receptor modulator and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate,
  • Obesity is not only a nutritional disorder in Western societies, it is also a serious health concern because of its association with adult-onset diabetes, hypertension, and heart disease (Grundy, 1990, Disease-a-Month 36:645-696). In addition, obesity is currently described by World Health Organization (WHO) as an epidemic in many industrialized nations. While there is evidence to suggest that body weight was physiologically regulated, the molecular mechanism has remained elusive. However, animal studies have produced several mouse strains that contain single-gene mutations, resulting in an obese phenotype. One such recessive mutation is manifested in the ob/ob mice, and it is referred to as the obese (ob) mutation.
  • WHO World Health Organization
  • the ob gene product (also known as Leptin), is a major adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure.
  • mice when normal mice received leptin, they also ate less than the untreated controls. More importantly, Campfield et al. (1995, Science 269:546-549) injected leptin directly into lateral ventricle, and observed a reduction in the animals' food intake, suggesting that leptin acts on central neuronal networks to regulate feeding behavior and energy balance. Thus, this result provides evidence that the leptin receptor (also known as OB-R) is expressed by cells in the brain. Additionally, several studies have shown that ob gene expression is actually increased in obese humans (Considine et al., 1995, J. Clin. Invest. 95:2986-2988; Lonnquist etal., 1995, Nature Med. 1:950; Hamilton etal., 1995, Nature Med. 1:953).
  • leptin is effective at controlling weight loss, food intake, and energy expenditure
  • modulating and/or controlling the levels of leptin is a useful therapeutic approach in treating preventing, inhibiting or reducing the incidence of obesity in subjects suffering from obesity.
  • Controlling the level of leptin may result in a loss of appetite, a reduction of food intake, and an increase in energy expenditure in the subj ect, and thus may contribute to the control and treatment of obesity.
  • Obesity if left unabated, can have dire health consequences, such as adult-onset diabetes (Type II diabetes), hypertension, heart disease, osteoarthritis, increased blood pressure, increased incidence of stroke, and accelerated morbidity and mortality.
  • Traditional approaches are urgently needed at both the basic science and clinical levels to treat obesity.
  • This invention relates to the prevention and treatment of obesity. More particularly, this invention relates to a method of a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity-associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes mellitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin; comprising administering a therapeutically effective amount of a selective androgen receptor modulator and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable
  • this invention relates to a method of treating a subject suffering from obesity, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to treat obesity in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of preventing, suppressing, inhibiting or reducing the incidence of obesity in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to prevent, suppress, inhibit or reduce the incidence of obesity in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of promoting, increasing or facilitating weight loss in a subj ect, comprising the step of administering to the subj ect a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to promote, increase or faciUtate weight loss in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of decreasing, suppressing, inhibiting or reducing appetite of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce the appetite of the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of altering the body composition of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the body composition of the subject.
  • SARM selective androgen receptor modulator
  • alteringthe body composition comprises altering the lean body mass, the fat firee body mass of the subject, or a combination thereof.
  • this invention relates to a method of altering lean body mass or fat firee body mass of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the lean body mass or fat free body mass of the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to amethod of converting fatto lean muscle in a subject, comprising the step of adi inistering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to convert fat to lean muscle in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of treating an obesity- associated metaboUc disorder in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to treat the obesity-associated metaboUc disorder in the subj ect.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of preventing, suppressing, inhibiting or reducing an obesity-associated metabolic disorder in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/oir its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to prevent, suppress, inhibit or reduce the obesity-associated metabolic disorder in the subject.
  • SARM selective androgen receptor modulator
  • the obesity-associated metaboUc disorder is hypertension, hi another embodiment, the disorder is osteoarthritis. In another embodiment, the disorder is Type II diabetes meUitus. In another embodiment, the disorder is increased blood pressure. In another embodiment, the disorder is stroke. In another embodiment, the disorder is heart disease.
  • this invention relates to a method of decreasing, suppressing, inhibiting or reducing adipogenesis in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce adipogenesis in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of altering stem ceU differentiation in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter stem ceU differentiation in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of altering the level of leptin in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the level of leptin in the subj ect.
  • SARM selective androgen receptor modulator
  • altering the level of leptin comprises decreasing the level of leptin in the subject.
  • this invention relates to a method of decreasing, suppressing, inhibiting or reducing the level of leptin in a subject, comprising the step of ad hiistering to the subj ect a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce the level of leptin in the subject.
  • SARM selective androgen receptor modulator
  • G is O or S
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • T is OH, OR, -NHCOCHs, or NHCOR
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;
  • Q is aUcyl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCBj, NHCOCFs, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR HSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
  • R is aUcyl, haloalkyl, dihaloalkyl, trihaloaU yl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and
  • Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ; or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the SARM compound, or any combination thereof.
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;
  • Q is alkyl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 ,
  • R is alkyl, haloaU yl, dihaloaUcyl, trihaloaU yl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH; or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the SARM compound, or any combination thereof.
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • G is O or S; Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ; T is OH, OR, -NHCOCHa, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloaUcyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aiyl, phenyl, F, Cl, Br, I, alkenyl or OH; A is a ring selected f om:
  • B is a ring selected from:
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN CR 3 or SnR 3 ;
  • Qi and Q 2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSRNHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO, OCN,
  • Q 3 and Q 4 are independently of each other a hydrogen, aUcyl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 ,NHCSCF 3 , NHCSRNHSO 2 CH 3 ,NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; Wi is O, NH, NR, NO or S; and W 2 is N or NO; or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the SARM compound, or any combination thereof.
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • G is O or S
  • T is OH, OR, -NHCOCHs, or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R 2 is F, Cl, Br, I, CH 3 , CF 3 , OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, aUcyl, arylaU yl, OR, NH 2 , NHR, NR 2 or SR;
  • R 3 is F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , SnR 3 , or R 3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
  • Z is NO 2 , CN, COR, COOH, or CONHR;
  • Y is CF 3 , F, Br, Cl, I, CN, or SnR 3 ;
  • Q is H, alkyl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 ,
  • R 2 is F, Cl, Br, I, CH 3 , CF 3 , OH, C ⁇ , ⁇ O 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, aryla&yl, OR, NH 2 , NHR, NR 2 or SR;
  • R 3 is F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , SnR , or R 3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
  • R is alkyl, haloalkyl, dihaloaUcyl, trihaloaU yl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
  • Z is NO 2 , CN, COR, COOH, or CONHR;
  • Y is CF 3 ⁇ F, Br, Cl, I, CN, or SnR 3 ;
  • Q is H, ah yl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCHj, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSRNHSO 2 CH 3 , NHSO 2 R, OH, OR, COR, OCOR, OSO 2 R, SO 2 R, SR
  • the SARM is an androgen receptor agonist. In another embodiment, the SARM is an androgen receptor antagonist.
  • the present invention provides a safe and effective method of treating, preventing, suppressing, inhibiting or reducing the incidence of obesity and/or an obesity- associated metaboUc disorder, controlling appetite and promoting weight loss, altering body composition including lean body mass and fat firee body mass, converting fat to lean muscle, blocking adipogenesis, altering stem ceU differentiation, and is particularly useful in treating subjects suffering from symptoms and signs caused by obesity, excessive appetite and overweight, and obesity-associated metaboUc disorders such as hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, and heart disease.
  • Figure 1 Effect of Compound VI on lean body mass in female rats. Rats were left untreated (intact) or ovariectomized (OVX), and were treated with 0, 0.1, 0.3, 0.5, 0.75 1.0 and 3.0 mg/day of compound VI, or treated with DHT or bicalutamide. The percent change in lean body mass is depicted in Figure 1 A. The absolute values of lean body mass (in grams) are depicted in Figure IB.
  • Figure 2 Effect of Compound VI on body fat in female rats. Rats were left untreated (intact) or ovariectomized (OVX), and were treated with 0, 0.1, 0.3, 0.5, 0.75 1.0 and 3.0 mg/day of compound NI, or treated with DHT or bicalutamide, and the percent change in body fat was deteimihed.
  • Figure 3 Effect of Compound NI on body weight in female rats. Rats were left untreated (intact) or ovariectomized (ONX), and were treated with 0, 0.1, 0.3, 0.5, 0.75 1.0 and3.0mg/day of compound VI, ortreatedwith DHT or bicalutamide, and the body weight was determined. DETAILED DESCRIPTION OF THE INVENTION
  • This invention relates to the prevention and " treatment of obesity. More particularly, this invention relates to a method of a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity-associated metaboUc disorder, for example hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and or j) altering the level of leptin; comprising administering a therapeutically effective amount of a selective androgen receptor modulator and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt
  • SARM compounds are a novel class of androgen receptor targeting agents ("ARTA"). that have previously been shown to be useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual Ubido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d)
  • ADAM Androgen receptor targeting agents
  • SARM compounds are useful for treating, preventing, suppressing, inhibiting or reducing the incidence of obesity and/or an obesity-associated metabolic disorder, controlling appetite and promoting weight loss, altering body composition including lean body mass and fat firee body mass, converting fat to lean muscle, blocking adipogenesis, altering stem cell differentiation and/or altering the level of leptin.
  • SARM compounds are particularly useful in treating subjects suffering from symptoms and signs caused by obesity, excessive appetite and overweight, and obesity- associated metaboUc disorders such as hypertension, osteoarthritis, Type II diabetes meltitus, increased blood pressure, stroke, and heart disease.
  • this- invention relates to a method of treating a subject suffering from obesity, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to treat obesity in the subj ect.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of preventing, suppressing, inhibiting or reducing the incidence of obesity in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to prevent, suppress, inhibit or reduce the incidence of obesity in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of promoting, increasing or facilitating weight loss in a subject, comprising the step of aclministering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to promote, increase or faciUtate weight loss in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of decreasing, suppressing, inhibiting or reducing appetite of a subject, comprising the step of administering to the subj ect a selective androgen receptor modulator (S RM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce the appetite of the subject.
  • S RM selective androgen receptor modulator
  • this invention relates to a method of altering the body composition of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the body composition of the subj ect.
  • SARM selective androgen receptor modulator
  • altering the body composition comprises altering the lean body mass, the fat free body mass of the subject, or a combination thereof.
  • this invention relates to a method of altering lean body mass or fat free body mass of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the lean body mass or fat free body mass of the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of converting fat to lean muscle in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to convert fat to lean muscle in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of treating an obesity- associated metabolic disorder in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to treat the obesity-associated metabolic disorder in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of preventing, suppressing, inhibiting or reducing an obesity-associated metabolic disorder in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to prevent, suppress, inhibit or reduce the obesity-associated metabolic disorder in the subject.
  • SARM selective androgen receptor modulator
  • the obesity-associated metaboUc disorder is hypertension.
  • the disorder is osteoarthritis.
  • the disorder is Type II diabetes meUitus.
  • the disorder is increased blood pressure.
  • the disorder is stroke.
  • the disorder is heart disease.
  • this invention relates to a method of decreasing, suppressing, inhibiting or reducing adipogenesis in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce adipogenesis in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of altering stem ceU differentiation in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter stem ceU differentiation in the subject.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of altering the level of leptin in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the level of leptin in the subject.
  • SARM selective androgen receptor modulator
  • altering the level of leptin comprises decreasing the level of leptin in the subject.
  • this invention relates to a method of decreasing, suppressing, inhibiting or reducing the level of leptin in a subj ect, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce the level of leptin in the subj ect.
  • SARM selective androgen receptor modulator
  • G is O or S
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • T is OH, OR, -NHCOCH 3 , or NHCOR
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;
  • Q is alkyl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSRNHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
  • Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 .
  • the SARM is an analog of the compound of formula I. In another embodiment, the SARM is a derivative of the compound of formula! In another embodiment, the SARM is an isomer of the compound of formula I. In another embodiment, the SARM is a metaboUte of the compound of formula I. In another embodiment, the SARM is a pharmaceuticaUy acceptable salt of the compound of formula I. In another embodiment, the SARM is a pharmaceutical product of the compound of formula I. In another embodiment, the SARM is a hydrate of the compound of formula I. In another embodiment, the SARM is an N-oxide of the compound of formula I. In another embodiment, the SARM is a crystal of the compound of formula I.
  • the SARM is a polymorph of the compound of formula I.
  • the SARM is a prodrug of the compound of formula I.
  • the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the compound of formula I.
  • the SARM compound is a compound of formula I wherein X is O.
  • the SARM compound is a compound of formula I wherein G is O.
  • the SARM compound is a compound of formula I wherein Z is NO 2 .
  • the SARM compound is a compound of formula I wherein Z is CN.
  • the SARM compound is a compound of formula I wherein Y is CF 3 .
  • the SARM compound is a compound of formula I wherein Q is NHCOCH . ha another embodiment, the SARM compound is a compound of formula I wherein Q is F.
  • the SARM compound is a compound of formula I wherein T is OH.
  • the SARM compound is a compound of formula I wherein Ri is CH 3 .
  • the substituents Z and Y can be in any position of the ring carrying these substituents (hereinafter "A ring").
  • the substituent Z is in the para position of the A ring.
  • the substituent Y is in the meta position of the A ring.
  • the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring.
  • the substituent Q can be in any position of the ring carrying this substituent (hereinafter "B ring"). In one embodiment, the substituent Q is in the para position of the B ring. In another embodiment, the substituent Q is NHCOCH 3 and is in the para position of the B ring. In another embodiment, the substituent Q is F and is in the para position of the B ring.
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;
  • Q is alkyl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSRNHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR,NCS, SCN,NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: c
  • R is aUyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
  • the SARM is an analog of the compound of formula II.
  • the SARM is a derivative of the compound of formula EL hi another embodiment, the SARM is an isomer of the compound of formula II.
  • the SARM is a metaboUte of the compound of formula II.
  • the SARM is a pharmaceuticaUy acceptable salt of the compound of formula ⁇ .
  • the SARM is a pharmaceutical product of the compound of formula II.
  • the SARM is a hydrate of the compound of formula II.
  • the SARM is an N-oxide of the compound of formula II.
  • the SARM is a crystal of the compound of formula II.
  • the SARM is a polymorph of the compound of formula II. In another embodiment, the SARM is a prodrug of the compound of formula II. In another embodiment, the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the compound of formula II.
  • the SARM compound is a compound of formula II wherein X is O. In another embodiment, the SARM compound is a compound of formula II wherein Z is NO 2 . In another embodiment, the SARM compound is a compound of formula II wherein Z is CN. In another embodiment, the SARM compound is a compound of formula II wherein Y is CF3. In another embodiment, the SARM compound is a compound of formula II wherein Q is NHCOCH 3 . In another embodiment, the SARM compound is a compound of formula II wherein Q is F.
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • A is a ring selected from:
  • X)AY r B is a ring selected from: wherein A and B cannot simultaneously be a benzene ring; Z is NO 2 , CN, COOH, COR, NHCOR or CONHR; Y is CF 3 , F, I, Br, Cl, CN CR 3 or SnR 3 ; Qi and Q 2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSRNHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO, OCN,
  • Q 3 and Q 4 are independently of each other ahydrogen, alkyl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH3, NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, ' OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSRNHSO 2 CH 3 ,NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • Wi O, NH, NR, NO or S;
  • W 2 is N or NO.
  • the SARM is an analog of the compound of formula HI. In another embodiment, the SARM is a derivative of the compound of formula HI. In another embodiment, the SARM is an isomer of the compound of formula HI. In another embodiment, the SARM is a metaboUte of the compound of formula HI. In another embodiment, the SARM is a pharmaceuticaUy acceptable salt of the compound of formula HI. In another embodiment, the SARM is a pharmaceutical product of the compound of formula HI. In another embodiment, the SARM is a hydrate of the compound of formula HI. In another embodiment, the SARM is an N-oxide of the compound of formula HI. In another embodiment, the SARM is a crystal of the compound of formula HI.
  • the SARM is a polymorph of the compound of formula HI. In another embodiment, the SARM is a prodrug of the compound of formula HI. In another embodiment, the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the compound of formula HI.
  • the SARM compound is a compound of formula HI wherein X is O. In another embodiment, the SARM compound is a compound of formula HI wherein G is O. In another embodiment, the SARM compound is a compound of formula I wherein T is OH. In another embodiment, the SARM compound is a compound of formula HI wherein Ri is CH3. In another embodiment, the SARM compound is a compound of formula HI wherein Z is NO 2 . In another embodiment, the SARM compound is a compound of formula HI wherein Z is CN. In another embodiment, the SARM compound is a compound of formula HI wherein Y is CF 3 . In another embodiment, the SARM compound is a compound of formula HI wherein Qi is NHCOCH3. In another embodiment, the SARM compound is a compound of formula HI wherein Qi is F.
  • the substituents Z and Y can be in any position of the ring carrying these substituents (hereinafter "A ring").
  • the substituent Z is in the para position of the A ring.
  • the substituent Y is in the meta position of the A ring.
  • the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring.
  • the substituents Qi and Q 2 can be in any position of the ring carrying these substituents (hereinafter "B ring").
  • the substituent Qi is in the para position of the B ring.
  • the subsituent is Q 2 is H.
  • the substituent Qi is in the para position of the B ring and the subsituent is Q 2 is H.
  • the substituent Qi is NHCOCH 3 and is in the para position of the B ring, and the substituent is Q 2 is H.
  • the substitutent Qi is F and is in the para position of the B ring, and the substituent Q 2 is H.
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • T is OH, OR, -NHCOCH3, or NHCOR;
  • R is alkyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R 2 is F, Cl, Br, I, CH 3 , CF 3 , OH, CN, NO 2 , NHCOCH3, NHCOCF3, NHCOR, alkyl, aiylalkyl, OR, NH 2 , NHR, NR or SR;
  • R 3 is F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , SnR 3 , or R 3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
  • Z is NO 2 , CN, COR, COOH, or CONHR;
  • Y is CF 3> F, Br, Cl, I, CN, or SnR 3 ;
  • Q is H, alkyl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH3, N ⁇ COCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO 2 CH 3 , NHSO 2 R, OH, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
  • the SARM is an analog of the compound of formula IV. In another embodiment, the SARM is a derivative of the compound of formula IV. In another embodiment, the SARM is an isomer of the compound of formula IV. In another embodiment, the SARM is a metaboUte of the compound of formula IV. In another embodiment, the SARM is a pharmaceuticaUy acceptable salt of the compound of formula IV. In another embodiment, the SARM is a pharmaceutical product of the compoimd of formula IV. In another embodiment, the SARM is a hydrate of the compoimd of formula IV. In another embodiment, the SARM is an N-oxide of the compound of formula IV. In another embodiment, the SARM is a crystal of the compound of formula IV.
  • the SARM is a polymorph of the compound of formula IV. In another embodiment, the SARM is a prodrug of the compound of formula IV. In another embodiment, the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the compound of formula IV.
  • the SARM compound is a compound of formula IV wherein X is 0. In another embodiment, the SARM compound is a compound of formula IV wherein G is O. In another embodiment, the SARM compound is a compound of formula
  • the SARM compound is a compound of formula IN wherein Z is ⁇ O 2 .
  • the SARM compound is a compound of formula IN wherein Z is C ⁇ .
  • the SARM compound is a compound of formula IN wherein Y is CF 3 .
  • the SARM compound is a compound of formula IN wherein Q is ⁇ HCOCH 3 .
  • the SARM compound is a compound of formula IN wherein Q is F.
  • the SARM compound is a compound of formula IN wherein T is
  • the SARM compound is a compound of formula IV wherein
  • Ri is CH 3 .
  • the SARM compound is a compound of formula IV wherein Q is F and R 2 is CH 3 .
  • the SARM compound is a compound of formula IV wherein Q is F and R 2 is Cl.
  • the substituents Z, Y and R 3 can be in any position of the ring carrying these substituents (hereinafter "A ring").
  • a ring the substituent Z is in the para position of the A ring.
  • the substituent Y is in the meta position of the A ring.
  • the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring.
  • the substituents Q and R 2 can be in any position of the ring carrying these substituents (hereinafter "B ring").
  • the substitutent Q is in the para position of the B ring.
  • the substitutent Q is in the para position of the B ring.
  • the substitutent Q is NHCOCH 3 and is in the para position of the B ring.
  • the substituents R 2 and R 3 are not limited to one particular substituent, and can be any combination of the substituents Usted above.
  • R 2 is F, Cl, Br, I, CH 3 , CF 3 , OH, CN, NO 2 , NHCOCH 3 ,
  • NHCOCF 3 NHCOR, alkyl, arylaU yl, OR, NH 2 , NHR, NR 2 or SR;
  • R 3 is F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , S11R3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
  • R is aUcyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
  • Z is NO 2 , CN, COR, COOH, or CONHR;
  • Y is CF 3 , F, Br, Cl, I, CN, or SnR 3 ;
  • Q is H, alkyl, F, Cl, Br, I, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH3, NHCOCF 3 , NHCORi NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSRNHSO 2 CH 3 , NHSO 2 R, OH, OR, COR, OCOR, OSO 2 R, SO 2 R, SR,NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
  • the SARM is an analog of the compound of formula V. In another embodiment, the SARM is a derivative of the compound of formula V. In another embodiment, the SARM is an isomer of the compound of formula V. In another embodiment, the SARM is a metabolite of the compound of formula V. In another embodiment, the SARM is a pharmaceutically acceptable salt of the compound of formula V. In another embodiment, the SARM is a pharmaceutical product of the compound of formula V. In another embodiment, the SARM is a hydrate of the compound of formula V. In another embodiment, the SARM is an N-oxide of the compound of formula V. In another embodiment, the SARM is a crystal of the compound of formula V.
  • the SARM is a polymorph of the compound of formula V. In another embodiment, the SARM is a prodrug of the compound of formula V. In another embodiment, the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, crystal, polymorph or prodrug of the compound of formula V.
  • the SARM is a compound of formula V wherein Z is NO 2 . In another embodiment, the SARM is a compound of formula V wherein Z is CN. In another embodiment, the SARM is a compound of formula V wherein Y is CF 3 . In another embodiment, the SARM is a compound of formula V wherein Q is NHCOCH 3 . In another embodiment, the SARM is a compound of formula V wherein Q is F. In another embodiment, the SARM is a compound of formula V wherein Q is F and R 2 is CH 3 . In another embodiment, the SARM is a compound of formula V wherein Q is F and R 2 is Cl.
  • the substituents Z, Y and R 3 can be in any position of the A ring, and the substituents Q and R 2 can be in any position of B ring, as discussed above for compound IV. Furthermore, as discussed above, when the integers m and n are greater than one, the substituents R and R 3 are not limited to one particular substituent, and can be any combination of the substituents Usted above.
  • the SARM is an analog of the compound of formula VI. In another embodiment, the SARM is a derivative of the compound of formula VI. In another embodiment, the SARM is an isomer of the compound of formula V! In another embodiment, the SARM is a metaboUte of the compound of formula VI. In another embodiment, the SARM is a pharmaceuticaUy acceptable salt of the compound of formula VI. In another embodiment, the SARM is a pharmaceutical product of the compound of formula VI. In another embodiment, the SARM is a hydrate of the compound of formula VI. In another embodiment, the SARM is an N-oxide of the compound of formula VI. In another embodiment, the SARM is a crystal of the compound of formula VI.
  • the SARM is a polymorph of the compound of formula VI.
  • the SARM is a prodrug of the compound of formula VI.
  • the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the compound of formula VI.
  • the SARM is an analog of the compound of formula VH. In another embodiment, the SARM is a derivative of the compound of formula VH. In another embodiment, the SARM is an isomer of the compound of formula VH. In another embodiment, the SARM is a metaboUte of the compound of formula VH. In another embodiment, the SARM is a pharmaceuticaUy acceptable salt of the compound of formula VH. In another embodiment, the SARM is a pharmaceutical product of the compound of formula VH. In another embodiment, the SARM is a hydrate of the compound of formula VH. In another embodiment, the SARM is an ⁇ -oxide of the compound of formula VH. In another embodiment, the SARM is a crystal of the compound of formula VH.
  • the SARM is a polymorph of the compound of formula VH.
  • the SARM is a prodrug of the compound of formula VH.
  • the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, ⁇ -oxide, crystal, polymorph or prodrug of the compound of formula VH.
  • the substituent R is defined herein as an aUcyl, haloaUcyl, dihaloaU yl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 ; aryl, phenyl, F, Cl, Br, I, alkenyl, or hydroxyl (OH).
  • an "aUcyl” group refers to a saturated aUphatic hydrocarbon, including straight- chain, branched-chain and cyclic alkyl groups.
  • the aUcyl group has 1- 12 carbons.
  • the alkyl group has 1-7 carbons.
  • the alkyl group has 1-6 carbons.
  • the aUcyl group has 1-4 carbons.
  • the alkyl group may be unsubstituted or substituted by one or more groups selected from halogen (e.g.
  • haloalkyl group refers to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g. by F, Cl, Br or !
  • halogen refers to elements of Group NH or the periodic table, e.g. F, Cl, Br or I.
  • aryl group refers to an aromatic group having at least one carbocycUc aromatic group or heterocycUc aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen (e.g. F, Cl, Br, I), haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, diaUcylamino, carboxy or thio or thioa cyl.
  • halogen e.g. F, Cl, Br, I
  • aryl rings are phenyl, naph ⁇ hyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, fhiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.
  • a "hydroxyl” group refers to an OH group.
  • An “alkenyl” group refers to a group having at least one carbon to carbon double bond.
  • arylalkyl refers to an alkyl bound to an aryl, wherein aUcyl and aryl are as defined above.
  • An example of an araUcyl group is a benzyl group.
  • the present invention relates to the use of a SARM compound and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, ⁇ -oxide, prodrug, polymorph or crystal or combinations thereof.
  • the invention relates to the use of an analog of the SARM compound.
  • the invention relates to the use of a derivative of the SARM compound.
  • the invention relates to the use of an isomer of the SARM compound.
  • the invention relates to the use of a metabolite of the SARM compound.
  • the invention relates to the use of a pharmaceuticaUy acceptable salt of the SARM compound, hi another embodiment, the invention relates to the use of a pharmaceutical product of the SARM compound. In another embodiment, the invention relates to the use of a hydrate of the SARM compound. In another embodiment, the invention relates to the use of an N-oxide of the SARM compound. In another embodiment, the invention relates to the use of aprodrug of the SARM compound. In another embodiment, the invention relates to the use of a polymorph of the SARM compound. In another embodiment, the invention relates to the use of a crystal of the SARM compound.
  • the invention relates to the use of any of a combination of an analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, or N- oxide, prodrug, polymorph or crystal of the SARM compounds of the present invention.
  • the term “isomer” includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.
  • this invention encompasses the use of various optical isomers of the SARM compounds.
  • the SARM compounds of the present invention contain at least one chiral center. Accordingly, the SARM compounds used in the methods of the present invention may exist in, and be isolated in, optically-active or racemic forms. Some compounds may also exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereroisomeric form, or mixtures thereof, which form possesses properties useful in the treatment of obesity and related disorders as described herein.
  • the SARM compounds are the pure (R)-isomers.
  • the SARM compounds are the pure (S)-isomers. In another embodiment, the SARM compounds are a mixture of the (R) and the (S) isomers. In another embodiment, the SARM compounds are a racemic rnixture comprising an equal amount of the (R) and the (S) isomers. It is weU known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystaUization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
  • the invention includes pharmaceuticaUy acceptable salts of amino-substituted compounds with organic and inorganic acids, for example, citric acid and hydrochloric acid.
  • the invention also includes N-oxides of the amino substituents of the compounds described herein.
  • PharmaceuticaUy acceptable salts can also be prepared from the phenolic compounds by treatment with inorganic bases, for example, sodium hydroxide.
  • esters of the phenoUc compounds can be made with aUphatic and aromatic carboxyUc acids, for example, acetic acid and benzoic acid esters.
  • This invention further includes derivatives of the SARM compounds.
  • derivatives includes but is not limited to ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like.
  • this invention further includes hydrates of the SARM compounds.
  • hydrate includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like.
  • This invention further includes pharmaceutical products of the SARM compounds.
  • pharmaceutical product means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.
  • This invention further includes prodrugs of the SARM compounds.
  • prodrug means a substance which can be converted in-vivo into a biologically active agent by such reactions as hydrolysis, esterification, desterification, activation, salt formation and the Uke.
  • This invention further includes crystals of the SARM compounds.
  • this invention provides polymorphs of the SARM compounds.
  • crystal means a substance in a crystalline state.
  • polymorph refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.
  • SARM compounds are a novel class of androgen receptor targeting agents ("ARTA"), that have previously been shown to be useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased Ubido, sexual dysfunction, erectUe dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual Ubido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia favorhair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment of a variety of hormone-related conditions, for example conditions
  • SARM compounds are also useful for a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or faciUtating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity-associated metaboUc disorder, for example hypertension, osteoarthritis, Type H diabetes meUitus, increased bloodpressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin; comprising administering a therapeutically effective amount of a selective androgen receptor modulator and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical
  • the SARM compounds of the present invention alter the levels of leptin in a subj ect.
  • the SARM compounds decrease the levels of leptin and are therefore inhibitors of leptin.
  • the SARM compounds of the present invention increase the levels of leptin in a subject.
  • leptin was shown to have an effect on appetite on weight loss in obese mice, and thus has been implicated in obesity (PeUeymounter et al., 1995, Halaas et al., 1995, Campfield et al., 1995).
  • leptin When leptin was injected into grossly obese mice, which possessed two mutant copies of the ob gene, the mice exhibited a reduced appetite and began to lose weight. In addition, leptin played a role in reducing the animals' food intake and in increasing their energy expenditure. Similarly, when normal mice received leptin, they also ate less than the untreated controls. Moreover, it has been suggested by Campfield et al that leptin acts on central neuronal networks to regulate feeding behavior and energy balance.
  • the term 'leptin inhibitor' refers to a SARM compound which decreases the level of leptin, so that the level of leptin after treatment with the SARM compound is lower than the level of leptin in the absence of the compoimd.
  • 'increasing the level of leptin' means that the levels of leptin after treatment with the SARM compound is higher than the level of leptin in the absence of the SARM compound.
  • the term 'level of leptin' refers to the serum level of leptin.
  • the SARM compounds of the present invention have an effect on leptin in-vitro and in-vivo.
  • Leptin levels can be measured by methods known to one skilled in the art, for example by commercially available ELISA kits. In addition, Leptin levels may be determined in in-vitro assays, or in in-vivo assays, by any method known to a person skilled in the art.
  • leptin Since leptin is impUcated in controlling appetite, weight loss, food intake, and energy expenditure, modulating and/or controUing the levels of leptin is a useful therapeutic approach in treating preventing, inhibiting or reducing the incidence of obesity in subjects suffering from obesity. Modulating the level of leptin can result in a loss of appetite, a reduction of food intake, and an increase in energy expenditure in the subject, and thus may contribute to the control and treatment of obesity.
  • the term "obesity" is defined as an increase in body weight beyond the limitation of skeletal and physical requirement, as the result of excessive accumulation of fat in the body.
  • osteoarthritis a disorder which results from, is a consequence of, is exacerbated by or is secondary to obesity.
  • Non-limiting examples of such a disorder are osteoarthritis, Type H diabetes meUitus, increased blood pressure, stroke, and heart disease.
  • osteoarthritis refers to a non-inflammatory degenerative joint disease occurring chiefly in older people, characterized by degeneration of the articular cartilage, hypertrophy of bones and the margins and changes in the synovia! membrane. It is accompanied by pain and stiffness, particularly after prolonged activity.
  • diabetes means a relative or absolute lack of insulin leading to uncontrolled carbohydrate metabolism. Most patients can be clinically classified as having either insulin-dependent diabetes mellitus (IDDM or Type-I diabetes) or non- insulin-dependent diabetes meUitus (NIDDM or Type-H diabetes).
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non- insulin-dependent diabetes meUitus
  • IPDDM insulin-dependent diabetes meUitus
  • IPDDM non- insulin-dependent diabetes meUitus
  • the term “increased blood pressure” or “hypertension” refers to a repeatedly high blood pressure above 140 over 90 mmHg. Chronically high blood pressure can cause blood vessel changes in the back of the eye, thickening of the heart muscle, kidney f-rilure, and brain damage.
  • stroke refers to damage to nerve cells in the brain due to insufficient blood supply often caused by a bursting blood vessel or a blood clot.
  • heart disease refers to a malfunction in the heart normal function and activity, including heart failure.
  • adipogenesis also referred to as “lipogenesis” refers to the production of fat, either fatty degeneration or fatty infiltration, and also covers the normal deposition of fat or the conversion of carbohydrate or protein to fat.
  • stem ceU refers to a cell that gives rise to a lineage of cells. In the process of stem cells differentiation, these ceUs divide to produce dissimilar daughter ceUs, one replacing the original stem cell, the other differentiating further to different lineages of cells.
  • the SARMs which are useful in preventing and treating obesity are classified as androgen receptor agonists (AR agonists) or androgen receptor antagonists (AR antagonists).
  • AR agonists androgen receptor agonists
  • AR antagonists androgen receptor antagonists
  • the AR is a ligand-activated transcriptional regulatory protein that mediates induction of male sexual development and function through its activity with endogenous androgens (male sex hormones).
  • the androgenic hormones are steroids which are produced in the body by the testis and the cortex of the adrenal gland. Androgenic steroids play an important role in many physiologic processes, including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth, spermatogenesis, and the male hair pattern (Matsumoto, Endocrinol. Met. Clin. N.
  • the endogenous steroidal androgens include testosterone and dihydrotestosterone ("DHT").
  • DHT dihydrotestosterone
  • Other steroidal androgens include esters of testosterone, such as the cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, and decanoate esters, and other synthetic androgens such as 7-Methyl- Nortestosterone ("MENT”) and its acetate ester (Sundaram et al., "7 Alpha-Methyl- Nortestosterone(MENT): The Optimal Androgen For Male Contraception," Ann. Med., 25:199-205 (1993) (“Sundaram”)).
  • a receptor agonist is a substance which binds receptors and activates them.
  • a receptor antagonist is a substance which binds receptors and inactivates them.
  • the SARMs which are useful in treating and preventing obesity and which modulate leptin levels are AR agonists, and are, therefore, useful in binding to and activating the AR.
  • the SARMs which are useful in treating and preventing obesity and which modulate leptin levels are AR antagonists, and are, therefore, useful in binding to and inactivating the AR.
  • Assays to determine whether the compounds of the present invention are AR agonists or antagonists are well known to a person skilled in the art.
  • AR agonistic activity can be determined by monitoring the ability of the SARM compounds to maintain and/or stimulate the growth of AR containing tissue such as prostate and seminal vesicles, as measured by weight.
  • AR antagonistic activity can be determined by monitoring the ability of the SARM compounds inhibit the growth of AR containing tissue.
  • the SARM compounds of the present invention can be classified as partial AR agonist/antagonists.
  • the SARMs are AR agonists in some tissues, to cause increased transcription of AR-responsive genes (e.g. muscle anabolic effect). In other tissues, these compounds serve as competitive inhibitors of testosterone/DHT on the AR to prevent agonistic effects of the native androgens.
  • the compounds of the present invention bind either reversibly or irreversibly to the androgen receptor.
  • the SARM compounds bind reversibly to the androgen receptor.
  • the SARM compounds bind irreversibly to the androgen receptor.
  • the compounds of the present invention may contain a functional group (affinity label) that allows aU ylation of the androgen receptor (i.e. covalent bond formation).
  • a functional group affinity label
  • contacting means that the SARM compound of the present mvention is introduced into a sample containing the protein or enzyme in a test tube, flask, tissue culture, chip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit binding of the SARM to the enzyme.
  • Methods for contacting the samples with the SARM or other specific binding components are known to those skilled in the art and may be selected depending on the type of assay protocol to be run. Incubation methods are also standard and are known to those skilled in the art.
  • the treatment methods of the present invention comprise, in one embodiment, administering a pharmaceutical preparation comprising the SARM compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymoi h, crystal or any combination thereof; and a pharmaceutically acceptable carrier.
  • pharmaceutical composition means a composition comprising an "effective amount" of the active ingredient, i.e. the SARM compound, together with a pharmaceutically acceptable carrier or diluent.
  • an “effective amount” as used herein refers to that amount which provides a therapeutic effect for a given condition and administration regimen.
  • An “effective amount” of the SARM compounds as used herein can be in the range of 1-500 mg/day. In one embodiment the dosage is in the range of 1 -100 mg/day. In another embodiment the dosage is in the range of 100-500 mg/day. In another embodiment the dosage is in a range of 45-60 mg/day. In another embodiment the dosage is in the range of 15-25 mg/day. In another embodiment the dosage is in the range of 55-65 mg/day. In another embodiment the dosage is in the range of 45-60 mg/day.
  • the SARM compounds can be administered daily, in single dosage forms containing the entire amount of daily dose, or can be administered daily in multiple doses such as twice daily or three times daUy.
  • the SARM compounds can also be administered mtermittently, for example every other day, 3 days a week, four days a week, five days a week and the like.
  • the term “treating” includes preventative as weU as disorder remitative treatment.
  • the terms “reducing”, “suppressing” and “inhibiting” have their commonly understood meaning of lessening or decreasing.
  • the term “facilitating” is giving its commonly understood meaning of increasing the rate.
  • the term “promoting” is given its commonly understood meaning of increasing.
  • progression means increasing in scope or severity, advancing, growing or becoming worse.
  • administering refers to bringing a subject in contact with a SARM compound of the present invention.
  • administration can be accomplished in vitro, i.e. in a test tube, or in vivo, i.e. in ceUs or tissues of living organisms, for example humans.
  • the present mvention encompasses administering the compounds of the present invention to a subject.
  • the subject is a mammalian subject. In another embodiment, the subject is a human.
  • compositions containing the SARM agent can be administered to a subject by any method known to a person sldUed in the art, such as parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermaUy, subcutaneously, intraperitonealy, intraventricularly, intracranially, intravaginally or intratumoraUy.
  • the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e. as a soUd or a Uquid preparation.
  • Suitable solid oral formulations include tablets, capsules, pUls, granules, pellets and the like.
  • Suitable Uquid oral formulations include solutions, suspensions, dispersions, emulstions, oils and the like.
  • the SARM compounds are formulated in a capsule.
  • the compositions of the present invention comprise in addition to the SARM active compound and the inert carrier or dUuent, a hard gelating capsule.
  • the pharmaceutical compositions are at ninistered by intravenous, intraarterial, or intramuscular injection of a Uquid preparation.
  • suitable liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the tike.
  • the pharmaceutical compositions are administered intravenously, and are thus formulated in a form suitable for intravenous administration.
  • the pharmaceutical compositions are administered intraarterially, and are thus formulated in a form suitable for intraarterial administration.
  • the pharmaceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for intramuscular adininistration.
  • the pharmaceutical compositions are a ⁇ ninistered topicaUy to body surfaces, and are thus formulated in a form suitable for topical administration.
  • Suitable topical formulations include gels, ointments, creams, lotions, drops and the like.
  • the SARM agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the tike are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.
  • the pharmaceutical compositions are administered as a suppository, for example a rectal suppository or a urethral suppository.
  • the pharmaceutical compositions are administered by subcutaneous implantation of a pellet.
  • the peUet provides for controlled release of SARM agent over a period of time.
  • the active compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid).
  • a liposome see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid).
  • pharmaceuticalaUy acceptable carriers or diluents are well known to those skilled in the art.
  • the carrier or dUuent may be a soUd carrier or diluent for solid formuations, a liquid carrier or diluent for Uquid formulations, or mixtures thereof.
  • Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • a gum e.g. corn starch, pregeletanized starch
  • a sugar e.g., lactose, mannitol, sucrose, dextrose
  • a cellulosic material e.g. microcrystalline cellulose
  • an acrylate e.g. polymethylacrylate
  • calcium carbonate e.g. polymethylacrylate
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcohoUc/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil.
  • Parenteral vehicles for subcutaneous, intravenous, intraarterial, or intramuscular injection
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the tike.
  • Examples are sterile liquids such as water and oUs, with or without the addition of a surfactant and other pharmaceuticaUy acceptable adjuvants.
  • Uquid carriers In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred Uquid carriers, particularly for injectable solutions.
  • oUs are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oU, mineral oil, olive oU, sunflower oil, and fish-liver oU.
  • compositions may further comprise binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl ceUulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g.
  • binders e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl ceUulose, hydroxypropyl methyl cellulose, povidone
  • disintegrating agents e.g.
  • cornstarch potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCI, acetate, phosphate) of various pH and ionic strength, additives such as albumin, or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g.
  • sodium lauryl sulfate permeation enhancers
  • solubilizing agents e.g., glycerol, polyethylene glycerol
  • anti-oxidants e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole
  • stabilizers e.g. hydroxypropyl ceUulose, hyroxypropyhnethyl cellulose
  • viscosity increasing agents e.g. carbomer, colloidal siUcon dioxide, ethyl ceUulose, guar gum
  • sweetners e.g.
  • aspartame, citric acid preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. coUoidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsif ⁇ ers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxarnines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.
  • lubricants e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate
  • flow-aids e.g. coUoidal silicon dioxide
  • the pharmaceutical compositions provided herein are controlled release compositions, i.e. compositions in which the SARM compound is released over a period of time after administration.
  • Controlled or sustained release compositions include formulation in UpophiUc depots (e.g. fatty acids, waxes, oUs).
  • the composition is an immediate release composition, i.e. a composition in which all of the SARM compoimd is released immediately after administration.
  • the pharmaceutical composition can be delivered in a controlled release system.
  • the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, Uposomes, or other modes of administration.
  • a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Bio ed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989).
  • polymeric materials can be used.
  • a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical AppUcations of Controlled
  • compositions may also include incorporation of the active material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycohc acid, hydrogels, etc, or onto Uposomes, microemulsions, miceUes, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.)
  • polymeric compounds such as polylactic acid, polglycohc acid, hydrogels, etc.
  • Uposomes microemulsions, miceUes, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.
  • particulate compositions coated with polymers e.g. poloxamers or poloxamines
  • the compound coupled to antibodies directed against tissue-specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors are also comprehended by the mvention.
  • Also comprehended by the invention are compounds modified by the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl ceUulose, dextran, polyvinyl alcohol, polyvinylpyrroUdone or polyproline.
  • the modified compounds are known to exhibit substantiaUy longer half-lives in blood foUowing intravenous inj ection than do the corresponding unmodified compounds (Abuchowski et al., 1981 ; Newmark et al, 1982; and Katre et al., 1987).
  • Such modifications may also increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stabUity of the compound, and greatly reduce the immunogenicity and reactivity of the compound.
  • the desired in vivo biological activity may be achieved by the administration of such polymer-compound abducts less frequently or in lower doses than with the unmodified compound.
  • compositions which contain an active component are well understood in the art, for example by mixing, granulating, or tablet- forming processes.
  • the active therapeutic ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient.
  • the SARM agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the tike are mixed with additives customary for this purpose, such as veliicles, stabilizers, or inert dUuents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oUy solutions.
  • the SARM agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are converted hito a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other.
  • An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms.
  • PharmaceuticaUy acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule), which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • the salts of the SARM wiU be pharmaceuticaUy acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric
  • the methods of the present invention comprise a ⁇ niimstering a SARM compound as the sole active ingredient.
  • methods or treating obesity as disclosed herein which comprise adixiinistering the SARM compounds in combination with one or more therapeutic agents.
  • agents include, hut are not limited to: LHRH analogs, reversible antiandrogens, antiestrogens, anticancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, or agents acting through other nuclear hormone receptors.
  • the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an LHRH analog.
  • the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with a reversible antiandiO en.
  • the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an antiestrogen.
  • the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an anticancer drug.
  • the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with a 5-alpha reductase inhibitor. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an aromatase inhibitor. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with a progestin. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in' combination with an agent acting through other nuclear hormone receptors.
  • Immature male Sprague-Dawleyrats (195-205 gram body weight) were used for this study. Animals were divided into groups of 15 animals (5 animals per time point) to receive one of the following treatments: (1) vehicle control, (2) testosterone propionate dissolved m vehicle solution at a dose of 500 ⁇ g/day, (3) Compound VI at dose of 500 ⁇ g/day dissolved in vehicle solution, or (4) Compound VH at dose of 500 ⁇ g/day dissolved in vehicle solution. All doses were delivered by subcutaneous placement of Alzet osmotic pumps. DaUy food intake was recorded for one-week and two-week studies.
  • Serum concentrations of testosterone (T), leptin, Insulin and IGF-1 were determined by commercially available ELISA kits. Serum concentration of Compound VI and Compoimd VH were determined by HPLC.
  • Compound VH had a more profound effect on serum leptin concentrations, suggesting it may affect animal body composition and other endocrine systems, such as the hypo ⁇ halamo-pituitary-IGF-1 axis and the reproductive axis.
  • Drug administration with Compound VI, bicalutamide (an antiandrogen), and/or DHT commenced on day 0 or 90 with the compound of interest administered via daily subcutaneous injection (0.20 mL) and continued until day 120 or 210 of the study.
  • Drug solutions were prepared daily by dissolving in DMSO and dilution with PEG 300. The percentage of DMSO was the same in aU vehicles (17.6%), as determined based on the solubility of the test compounds.
  • FIG. 1 A shows the percent change in lean body mass.
  • Figure IB shows the absolute values of lean body mass (in grams).
  • the high dose (3 mg/day) of Compound Nl-t eated group showed 9% increase in lean mass (Figure 1 A), as compared to the ovariectomized (OVX) control group at the 90 day time point. Similar trends were observed for aU dose groups.

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Abstract

This invention relates to the prevention and treatment of obesity. More particularly, this invention relates to a method of: a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition, e) altering lean body mass or fat free body mass, f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity-associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes mellitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin; comprising administering a therapeutically effective amount of a selective androgen receptor modulator and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, as described herein.

Description

TREATING OBESITY WITH SELECTIVE ANDROGEN RECEPTOR
MODULATORS
FIELD OF INVENTION
[0001] This invention relates to the prevention and treatment of obesity. More particularly, this invention relates to a method of a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat firee body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes mellitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin; comprising administering a therapeutically effective amount of a selective androgen receptor modulator and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof.
BACKGROUND OF THE INVENTION
[0002] Obesity is not only a nutritional disorder in Western societies, it is also a serious health concern because of its association with adult-onset diabetes, hypertension, and heart disease (Grundy, 1990, Disease-a-Month 36:645-696). In addition, obesity is currently described by World Health Organization (WHO) as an epidemic in many industrialized nations. While there is evidence to suggest that body weight was physiologically regulated, the molecular mechanism has remained elusive. However, animal studies have produced several mouse strains that contain single-gene mutations, resulting in an obese phenotype. One such recessive mutation is manifested in the ob/ob mice, and it is referred to as the obese (ob) mutation.
[0003] The ob gene product, (also known as Leptin), is a major adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure.
[0004] In an effort to understand the physiologic function of the ob gene, several independent research groups produced recombinant ob gene product in bacteria for in- vivo testing (Pelleymounter et al., 1995, Science 269:540-543; Halaas- et al., 1995, Science 269:543-546; Campfield et al., 1995, Science 269:546-549). When the Ob protein (also known as leptin) was injected into grossly obese mice, which possessed two mutant copies of the ob gene, the mice exhibited a reduced appetite and began to lose weight. In addition, these studies described a dual action of leptin in both reducing the animals' food intake and in increasing their energy expenditure. Similarly, when normal mice received leptin, they also ate less than the untreated controls. More importantly, Campfield et al. (1995, Science 269:546-549) injected leptin directly into lateral ventricle, and observed a reduction in the animals' food intake, suggesting that leptin acts on central neuronal networks to regulate feeding behavior and energy balance. Thus, this result provides evidence that the leptin receptor (also known as OB-R) is expressed by cells in the brain. Additionally, several studies have shown that ob gene expression is actually increased in obese humans (Considine et al., 1995, J. Clin. Invest. 95:2986-2988; Lonnquist etal., 1995, Nature Med. 1:950; Hamilton etal., 1995, Nature Med. 1:953).
[0005] Since leptin is effective at controlling weight loss, food intake, and energy expenditure, modulating and/or controlling the levels of leptin is a useful therapeutic approach in treating preventing, inhibiting or reducing the incidence of obesity in subjects suffering from obesity. Controlling the level of leptin may result in a loss of appetite, a reduction of food intake, and an increase in energy expenditure in the subj ect, and thus may contribute to the control and treatment of obesity.
[0006] Obesity, if left unabated, can have dire health consequences, such as adult-onset diabetes (Type II diabetes), hypertension, heart disease, osteoarthritis, increased blood pressure, increased incidence of stroke, and accelerated morbidity and mortality. Innovative approaches are urgently needed at both the basic science and clinical levels to treat obesity.
SUMMARY OF THE INVENTION [0007] This invention relates to the prevention and treatment of obesity. More particularly, this invention relates to a method of a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity-associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes mellitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin; comprising administering a therapeutically effective amount of a selective androgen receptor modulator and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, as described herein.
[0008] In one embodiment, this invention relates to a method of treating a subject suffering from obesity, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to treat obesity in the subject.
[0009] In another embodiment, this invention relates to a method of preventing, suppressing, inhibiting or reducing the incidence of obesity in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to prevent, suppress, inhibit or reduce the incidence of obesity in the subject.
[00010] In another embodiment, this invention relates to a method of promoting, increasing or facilitating weight loss in a subj ect, comprising the step of administering to the subj ect a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to promote, increase or faciUtate weight loss in the subject.
[00011] In another embodiment, this invention relates to a method of decreasing, suppressing, inhibiting or reducing appetite of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce the appetite of the subject.
[00012] In another embodiment, this invention relates to a method of altering the body composition of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the body composition of the subject. In one embodiment, alteringthe body composition comprises altering the lean body mass, the fat firee body mass of the subject, or a combination thereof.
[00013] In another embodiment, this invention relates to a method of altering lean body mass or fat firee body mass of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the lean body mass or fat free body mass of the subject.
[00014] In another embodiment, this invention relates to amethod of converting fatto lean muscle in a subject, comprising the step of adi inistering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to convert fat to lean muscle in the subject.
[00015] In another embodiment, this invention relates to a method of treating an obesity- associated metaboUc disorder in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to treat the obesity-associated metaboUc disorder in the subj ect.
[00016] In another embodiment, this invention relates to a method of preventing, suppressing, inhibiting or reducing an obesity-associated metabolic disorder in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/oir its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to prevent, suppress, inhibit or reduce the obesity-associated metabolic disorder in the subject.
[00017] In one embodiment, the obesity-associated metaboUc disorder is hypertension, hi another embodiment, the disorder is osteoarthritis. In another embodiment, the disorder is Type II diabetes meUitus. In another embodiment, the disorder is increased blood pressure. In another embodiment, the disorder is stroke. In another embodiment, the disorder is heart disease. [00018] In another embodiment, this invention relates to a method of decreasing, suppressing, inhibiting or reducing adipogenesis in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce adipogenesis in the subject.
[00019] In another embodiment, this invention relates to a method of altering stem ceU differentiation in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter stem ceU differentiation in the subject.
[00020] In another embodiment, this invention relates to a method of altering the level of leptin in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the level of leptin in the subj ect. In one embodiment, altering the level of leptin comprises decreasing the level of leptin in the subject.
[00021] In another embodiment, this invention relates to a method of decreasing, suppressing, inhibiting or reducing the level of leptin in a subject, comprising the step of ad hiistering to the subj ect a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce the level of leptin in the subject.
[00022] In one embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or faciUtating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat firee body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula I.
I wherein G is O or S;
X is a bond, O, CH2, NH, Se, PR, NO or NR;
T is OH, OR, -NHCOCHs, or NHCOR
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCBj, NHCOCFs, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR HSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is aUcyl, haloalkyl, dihaloalkyl, trihaloaU yl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the SARM compound, or any combination thereof.
[00023] h another embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat firee body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes mellitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem ceU differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula II.
π
wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2,
NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3,
NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR,NCS, SCN,NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is alkyl, haloaU yl, dihaloaUcyl, trihaloaU yl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the SARM compound, or any combination thereof.
[00024] hi another embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes mellitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem ceU differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula HI.
m wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S; Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCHa, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aiyl, phenyl, F, Cl, Br, I, alkenyl or OH; A is a ring selected f om:
B is a ring selected from:
wherein A and B cannot simultaneously be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN CR3 or SnR3;
Qi and Q2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
Q3 and Q4 are independently of each other a hydrogen, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3,NHCSCF3, NHCSRNHSO2CH3,NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; Wi is O, NH, NR, NO or S; and W2 is N or NO; or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the SARM compound, or any combination thereof.
[00025] In another embodiment, the SARM that is useful in a) treating, preventing, suppressmg, inhibiting, or reducing obesity; b) promoting, increasing or faciUtating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat firee body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metaboUc disorder, for example hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem ceU differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula IV.
IV wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
T is OH, OR, -NHCOCHs, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, aUcyl, arylaU yl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO2, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3; Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2,
NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and m is an integer of 1 -3 ; or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the SARM compound, or any combination thereof.
[00026] hi another embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitatmg weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat firee body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metaboUc disorder, for example hypertension, osteoarthritis, Type LI diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula N.
N wherein
R2 is F, Cl, Br, I, CH3, CF3, OH, CΝ, ΝO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, aryla&yl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR , or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is alkyl, haloalkyl, dihaloaUcyl, trihaloaU yl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; Z is NO2, CN, COR, COOH, or CONHR; Y is CF3ι F, Br, Cl, I, CN, or SnR3; Q is H, ah yl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCHj, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and m is an integer of 1-3; or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the SARM compound, or any combination thereof.
[00027] In another embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or faciUtating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metaboUc disorder, for example hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula NI or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, Ν-oxide, crystal, polymorph or prodrug of the SARM compound, or any combination thereof
NI [00028] In another embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or faciUtating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat firee body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula NH or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, Ν-oxide, crystal, polymorph or prodrug of the SARM compound, or any combination thereof.
Nπ
[00029] In another embodiment, the SARM is an androgen receptor agonist. In another embodiment, the SARM is an androgen receptor antagonist.
[00030] The present invention provides a safe and effective method of treating, preventing, suppressing, inhibiting or reducing the incidence of obesity and/or an obesity- associated metaboUc disorder, controlling appetite and promoting weight loss, altering body composition including lean body mass and fat firee body mass, converting fat to lean muscle, blocking adipogenesis, altering stem ceU differentiation, and is particularly useful in treating subjects suffering from symptoms and signs caused by obesity, excessive appetite and overweight, and obesity-associated metaboUc disorders such as hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, and heart disease.
BRIEF DESCRIPTION OF THE FIGURES
[00031 ] The present invention wiU be understood and appreciated more fuUy from the following detailed description taken in conjunction with the appended figures which depict:
Figure 1: Effect of Compound VI on lean body mass in female rats. Rats were left untreated (intact) or ovariectomized (OVX), and were treated with 0, 0.1, 0.3, 0.5, 0.75 1.0 and 3.0 mg/day of compound VI, or treated with DHT or bicalutamide. The percent change in lean body mass is depicted in Figure 1 A. The absolute values of lean body mass (in grams) are depicted in Figure IB.
Figure 2: Effect of Compound VI on body fat in female rats. Rats were left untreated (intact) or ovariectomized (OVX), and were treated with 0, 0.1, 0.3, 0.5, 0.75 1.0 and 3.0 mg/day of compound NI, or treated with DHT or bicalutamide, and the percent change in body fat was deteimihed.
Figure 3: Effect of Compound NI on body weight in female rats. Rats were left untreated (intact) or ovariectomized (ONX), and were treated with 0, 0.1, 0.3, 0.5, 0.75 1.0 and3.0mg/day of compound VI, ortreatedwith DHT or bicalutamide, and the body weight was determined. DETAILED DESCRIPTION OF THE INVENTION
[00032] This invention relates to the prevention and" treatment of obesity. More particularly, this invention relates to a method of a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity-associated metaboUc disorder, for example hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and or j) altering the level of leptin; comprising administering a therapeutically effective amount of a selective androgen receptor modulator and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, phaπnaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, as described herein.
[00033] Selective androgen receptor modulator (SARM) compounds are a novel class of androgen receptor targeting agents ("ARTA"). that have previously been shown to be useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual Ubido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic muscular wasting conditions; e) preventing and/or treating dry eye conditions; f) oral androgen replacement therapy; g) decreasing the incidence of, halting or causing a regression of prostate cancer; and/or h) inducing apoptosis h a cancer ceU. [00034] As demonstrated herein, SARM compounds are useful for treating, preventing, suppressing, inhibiting or reducing the incidence of obesity and/or an obesity-associated metabolic disorder, controlling appetite and promoting weight loss, altering body composition including lean body mass and fat firee body mass, converting fat to lean muscle, blocking adipogenesis, altering stem cell differentiation and/or altering the level of leptin. SARM compounds are particularly useful in treating subjects suffering from symptoms and signs caused by obesity, excessive appetite and overweight, and obesity- associated metaboUc disorders such as hypertension, osteoarthritis, Type II diabetes meltitus, increased blood pressure, stroke, and heart disease.
[00035] Accordingly, in one embodiment, this- invention relates to a method of treating a subject suffering from obesity, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to treat obesity in the subj ect.
[00036] In another embodiment, this invention relates to a method of preventing, suppressing, inhibiting or reducing the incidence of obesity in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to prevent, suppress, inhibit or reduce the incidence of obesity in the subject.
[00037] In another embodiment, this invention relates to a method of promoting, increasing or facilitating weight loss in a subject, comprising the step of aclministering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to promote, increase or faciUtate weight loss in the subject.
[00038] In another embodiment, this invention relates to a method of decreasing, suppressing, inhibiting or reducing appetite of a subject, comprising the step of administering to the subj ect a selective androgen receptor modulator (S RM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce the appetite of the subject.
[00039] In another embodiment, this invention relates to a method of altering the body composition of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the body composition of the subj ect. In one embodiment, altering the body composition comprises altering the lean body mass, the fat free body mass of the subject, or a combination thereof.
[00040] In another embodiment, this invention relates to a method of altering lean body mass or fat free body mass of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the lean body mass or fat free body mass of the subject.
[00041 ] In another embodiment, this invention relates to a method of converting fat to lean muscle in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to convert fat to lean muscle in the subject.
[00042] In another embodiment, this invention relates to a method of treating an obesity- associated metabolic disorder in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to treat the obesity-associated metabolic disorder in the subject.
[00043] In another embodiment, this invention relates to a method of preventing, suppressing, inhibiting or reducing an obesity-associated metabolic disorder in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to prevent, suppress, inhibit or reduce the obesity-associated metabolic disorder in the subject.
[00044] In one embodiment, the obesity-associated metaboUc disorder is hypertension. In another embodiment, the disorder is osteoarthritis. In another embodiment, the disorder is Type II diabetes meUitus. In another embodiment, the disorder is increased blood pressure. In another embodiment, the disorder is stroke. In another embodiment, the disorder is heart disease.
[00045] In another embodiment, this invention relates to a method of decreasing, suppressing, inhibiting or reducing adipogenesis in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce adipogenesis in the subject. [00046] hi another embodiment, this invention relates to a method of altering stem ceU differentiation in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter stem ceU differentiation in the subject.
[00047] In another embodiment, this invention relates to a method of altering the level of leptin in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the level of leptin in the subject. In one embodiment, altering the level of leptin comprises decreasing the level of leptin in the subject.
[00048] In another embodiment, this invention relates to a method of decreasing, suppressing, inhibiting or reducing the level of leptin in a subj ect, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce the level of leptin in the subj ect.
[00049] In one embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facUitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, mhibitmg or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula I.
I wherein G is O or S;
X is a bond, O, CH2, NH, Se, PR, NO or NR;
T is OH, OR, -NHCOCH3, or NHCOR
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.
[00050] In one embodiment, the SARM is an analog of the compound of formula I. In another embodiment, the SARM is a derivative of the compound of formula! In another embodiment, the SARM is an isomer of the compound of formula I. In another embodiment, the SARM is a metaboUte of the compound of formula I. In another embodiment, the SARM is a pharmaceuticaUy acceptable salt of the compound of formula I. In another embodiment, the SARM is a pharmaceutical product of the compound of formula I. In another embodiment, the SARM is a hydrate of the compound of formula I. In another embodiment, the SARM is an N-oxide of the compound of formula I. In another embodiment, the SARM is a crystal of the compound of formula I. h another embodiment, the SARM is a polymorph of the compound of formula I. In another embodiment, the SARM is a prodrug of the compound of formula I. In another embodiment, the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the compound of formula I.
[00051 ] In one embodiment, the SARM compound is a compound of formula I wherein X is O. hi one embodiment, the SARM compound is a compound of formula I wherein G is O. In another embodiment, the SARM compound is a compound of formula I wherein Z is NO2. In another embodiment, the SARM compound is a compound of formula I wherein Z is CN. In another embodiment, the SARM compound is a compound of formula I wherein Y is CF3. In another embodiment, the SARM compound is a compound of formula I wherein Q is NHCOCH . ha another embodiment, the SARM compound is a compound of formula I wherein Q is F. In another embodiment, the SARM compound is a compound of formula I wherein T is OH. In another embodiment, the SARM compound is a compound of formula I wherein Ri is CH3.
[00052] The substituents Z and Y can be in any position of the ring carrying these substituents (hereinafter "A ring"). In one embodiment, the substituent Z is in the para position of the A ring. In another embodiment, the substituent Y is in the meta position of the A ring. In another embodiment, the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring.
[00053] The substituent Q can be in any position of the ring carrying this substituent (hereinafter "B ring"). In one embodiment, the substituent Q is in the para position of the B ring. In another embodiment, the substituent Q is NHCOCH3 and is in the para position of the B ring. In another embodiment, the substituent Q is F and is in the para position of the B ring.
[00054] In another embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or faciUtating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metaboUc disorder, for example hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem ceU differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula II.
π
wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR,NCS, SCN,NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: c
R is aUyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
[00055] In one embodiment, the SARM is an analog of the compound of formula II. In another embodiment, the SARM is a derivative of the compound of formula EL hi another embodiment, the SARM is an isomer of the compound of formula II. In another embodiment, the SARM is a metaboUte of the compound of formula II. In another embodiment, the SARM is a pharmaceuticaUy acceptable salt of the compound of formula π. In another embodiment, the SARM is a pharmaceutical product of the compound of formula II. In another embodiment, the SARM is a hydrate of the compound of formula II. In another embodiment, the SARM is an N-oxide of the compound of formula II. In another embodiment, the SARM is a crystal of the compound of formula II. In another embodiment, the SARM is a polymorph of the compound of formula II. In another embodiment, the SARM is a prodrug of the compound of formula II. In another embodiment, the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the compound of formula II.
[00056] In one embodiment, the SARM compound is a compound of formula II wherein X is O. In another embodiment, the SARM compound is a compound of formula II wherein Z is NO2. In another embodiment, the SARM compound is a compound of formula II wherein Z is CN. In another embodiment, the SARM compound is a compound of formula II wherein Y is CF3. In another embodiment, the SARM compound is a compound of formula II wherein Q is NHCOCH3. In another embodiment, the SARM compound is a compound of formula II wherein Q is F. [00057] In another embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or faciUtating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem ceU differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula HI.
m wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Gis O or S; Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; A is a ring selected from:
X)AY r B is a ring selected from: wherein A and B cannot simultaneously be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN CR3 or SnR3; Qi and Q2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
Q3 and Q4 are independently of each other ahydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, ' OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3,NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
Wi is O, NH, NR, NO or S; and
W2 is N or NO.
[00058] In one embodiment, the SARM is an analog of the compound of formula HI. In another embodiment, the SARM is a derivative of the compound of formula HI. In another embodiment, the SARM is an isomer of the compound of formula HI. In another embodiment, the SARM is a metaboUte of the compound of formula HI. In another embodiment, the SARM is a pharmaceuticaUy acceptable salt of the compound of formula HI. In another embodiment, the SARM is a pharmaceutical product of the compound of formula HI. In another embodiment, the SARM is a hydrate of the compound of formula HI. In another embodiment, the SARM is an N-oxide of the compound of formula HI. In another embodiment, the SARM is a crystal of the compound of formula HI. In another embodiment, the SARM is a polymorph of the compound of formula HI. In another embodiment, the SARM is a prodrug of the compound of formula HI. In another embodiment, the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the compound of formula HI.
[00059] In one embodiment, the SARM compound is a compound of formula HI wherein X is O. In another embodiment, the SARM compound is a compound of formula HI wherein G is O. In another embodiment, the SARM compound is a compound of formula I wherein T is OH. In another embodiment, the SARM compound is a compound of formula HI wherein Ri is CH3. In another embodiment, the SARM compound is a compound of formula HI wherein Z is NO2. In another embodiment, the SARM compound is a compound of formula HI wherein Z is CN. In another embodiment, the SARM compound is a compound of formula HI wherein Y is CF3. In another embodiment, the SARM compound is a compound of formula HI wherein Qi is NHCOCH3. In another embodiment, the SARM compound is a compound of formula HI wherein Qi is F.
[00060] The substituents Z and Y can be in any position of the ring carrying these substituents (hereinafter "A ring"). In one embodiment, the substituent Z is in the para position of the A ring. In another embodiment, the substituent Y is in the meta position of the A ring. In another embodiment, the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring.
[00061] The substituents Qi and Q2 can be in any position of the ring carrying these substituents (hereinafter "B ring"). In one embodiment, the substituent Qi is in the para position of the B ring. In another embodiment, the subsituent is Q2 is H. In another embodiment, the substituent Qi is in the para position of the B ring and the subsituent is Q2 is H. In another embodiment, the substituent Qi is NHCOCH3 and is in the para position of the B ring, and the substituent is Q2 is H. In another embodiment, the substitutent Qi is F and is in the para position of the B ring, and the substituent Q2 is H.
[00062] In another embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metabolic disorder, for example hypertension, osteoarthritis, Type H diabetes mellitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem ceU differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula IV.
IV wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Gis O or S;
T is OH, OR, -NHCOCH3, or NHCOR;
R is alkyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, aiylalkyl, OR, NH2, NHR, NR or SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3> F, Br, Cl, I, CN, or SnR3;
Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NΗCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and m is an integer of 1-3.
[00063] In one embodiment, the SARM is an analog of the compound of formula IV. In another embodiment, the SARM is a derivative of the compound of formula IV. In another embodiment, the SARM is an isomer of the compound of formula IV. In another embodiment, the SARM is a metaboUte of the compound of formula IV. In another embodiment, the SARM is a pharmaceuticaUy acceptable salt of the compound of formula IV. In another embodiment, the SARM is a pharmaceutical product of the compoimd of formula IV. In another embodiment, the SARM is a hydrate of the compoimd of formula IV. In another embodiment, the SARM is an N-oxide of the compound of formula IV. In another embodiment, the SARM is a crystal of the compound of formula IV. In another embodiment, the SARM is a polymorph of the compound of formula IV. In another embodiment, the SARM is a prodrug of the compound of formula IV. In another embodiment, the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the compound of formula IV.
[00064]' In one embodiment, the SARM compound is a compound of formula IV wherein X is 0. In another embodiment, the SARM compound is a compound of formula IV wherein G is O. In another embodiment, the SARM compound is a compound of formula
IN wherein Z is ΝO2. In another embodiment, the SARM compound is a compound of formula IN wherein Z is CΝ. In another embodiment, the SARM compound is a compound of formula IN wherein Y is CF3. In another embodiment, the SARM compound is a compound of formula IN wherein Q is ΝHCOCH3. In another embodiment, the SARM compound is a compound of formula IN wherein Q is F. In another embodiment, the SARM compound is a compound of formula IN wherein T is
OH. In another embodiment, the SARM compound is a compound of formula IV wherein
Ri is CH3. In another embodiment, the SARM compound is a compound of formula IV wherein Q is F and R2 is CH3. In another embodiment, the SARM compound is a compound of formula IV wherein Q is F and R2 is Cl.
[0001] The substituents Z, Y and R3 can be in any position of the ring carrying these substituents (hereinafter "A ring"). In one embodiment, the substituent Z is in the para position of the A ring. In another embodiment, the substituent Y is in the meta position of the A ring. In another embodiment, the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring.
[0002] The substituents Q and R2 can be in any position of the ring carrying these substituents (hereinafter "B ring"). In one embodiment, the substitutent Q is in the para position of the B ring. In another embodiment, the substitutent Q is in the para position of the B ring. In another embodiment, the substitutent Q is NHCOCH3 and is in the para position of the B ring.
[0003] As contemplated herein, when the integers m and n are greater than one, the substituents R2 and R3 are not limited to one particular substituent, and can be any combination of the substituents Usted above.
[00065] In another embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or faciUtating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metaboUc disorder, for example hypertension, osteoarthritis, Type H diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem ceU differentiation; and/or j) altering the level of leptin, is a compound represented by the structure of formula V.
V wherein
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3,
NHCOCF3, NHCOR, alkyl, arylaU yl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, S11R3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is aUcyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; Z is NO2, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCORi NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR,NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and m is an integer of 1-3.
[00066] In one embodiment, the SARM is an analog of the compound of formula V. In another embodiment, the SARM is a derivative of the compound of formula V. In another embodiment, the SARM is an isomer of the compound of formula V. In another embodiment, the SARM is a metabolite of the compound of formula V. In another embodiment, the SARM is a pharmaceutically acceptable salt of the compound of formula V. In another embodiment, the SARM is a pharmaceutical product of the compound of formula V. In another embodiment, the SARM is a hydrate of the compound of formula V. In another embodiment, the SARM is an N-oxide of the compound of formula V. In another embodiment, the SARM is a crystal of the compound of formula V. In another embodiment, the SARM is a polymorph of the compound of formula V. In another embodiment, the SARM is a prodrug of the compound of formula V. In another embodiment, the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N- oxide, crystal, polymorph or prodrug of the compound of formula V.
[00067] In another embodiment, the SARM is a compound of formula V wherein Z is NO2. In another embodiment, the SARM is a compound of formula V wherein Z is CN. In another embodiment, the SARM is a compound of formula V wherein Y is CF3. In another embodiment, the SARM is a compound of formula V wherein Q is NHCOCH3. In another embodiment, the SARM is a compound of formula V wherein Q is F. In another embodiment, the SARM is a compound of formula V wherein Q is F and R2 is CH3. In another embodiment, the SARM is a compound of formula V wherein Q is F and R2 is Cl.
[00068] The substituents Z, Y and R3 can be in any position of the A ring, and the substituents Q and R2 can be in any position of B ring, as discussed above for compound IV. Furthermore, as discussed above, when the integers m and n are greater than one, the substituents R and R3 are not limited to one particular substituent, and can be any combination of the substituents Usted above.
[00069] the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or faciUtating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity-associated metaboUc disorder, for example hypertension, osteoarthritis, Type H diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin, is a compoimd represented by the structure of formula VI.
VI
[00070] In one embodiment, the SARM is an analog of the compound of formula VI. In another embodiment, the SARM is a derivative of the compound of formula VI. In another embodiment, the SARM is an isomer of the compound of formula V! In another embodiment, the SARM is a metaboUte of the compound of formula VI. In another embodiment, the SARM is a pharmaceuticaUy acceptable salt of the compound of formula VI. In another embodiment, the SARM is a pharmaceutical product of the compound of formula VI. In another embodiment, the SARM is a hydrate of the compound of formula VI. In another embodiment, the SARM is an N-oxide of the compound of formula VI. In another embodiment, the SARM is a crystal of the compound of formula VI. In another embodiment, the SARM is a polymorph of the compound of formula VI. In another embodiment, the SARM is a prodrug of the compound of formula VI. In another embodiment, the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of the compound of formula VI.
[00071] h another embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity- associated metaboUc disorder, for example hypertension, osteoarthritis, Type H diabetes meUitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; andor j) altering the level of leptin, is a compound represented by the structure of formula VH.
NH
[00072] In one embodiment, the SARM is an analog of the compound of formula VH. In another embodiment, the SARM is a derivative of the compound of formula VH. In another embodiment, the SARM is an isomer of the compound of formula VH. In another embodiment, the SARM is a metaboUte of the compound of formula VH. In another embodiment, the SARM is a pharmaceuticaUy acceptable salt of the compound of formula VH. In another embodiment, the SARM is a pharmaceutical product of the compound of formula VH. In another embodiment, the SARM is a hydrate of the compound of formula VH. In another embodiment, the SARM is an Ν-oxide of the compound of formula VH. In another embodiment, the SARM is a crystal of the compound of formula VH. In another embodiment, the SARM is a polymorph of the compound of formula VH. In another embodiment, the SARM is a prodrug of the compound of formula VH. ha another embodiment, the SARM is a combination of any of an analog, derivative, metaboUte, isomer, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, Ν-oxide, crystal, polymorph or prodrug of the compound of formula VH.
[00073] The substituent R is defined herein as an aUcyl, haloaUcyl, dihaloaU yl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3; aryl, phenyl, F, Cl, Br, I, alkenyl, or hydroxyl (OH).
[00074] An "aUcyl" group refers to a saturated aUphatic hydrocarbon, including straight- chain, branched-chain and cyclic alkyl groups. In one embodiment, the aUcyl group has 1- 12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the aUcyl group has 1-4 carbons. The alkyl group may be unsubstituted or substituted by one or more groups selected from halogen (e.g. F, Cl, Br, I), hydroxy, alkoxy carbonyl, amido, aUcylamido, diaUcylamido, nitro, amino, alkylamino, diaUcylamino, carboxyl, thio and thioalkyl.
[00075] A "haloalkyl" group refers to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g. by F, Cl, Br or ! A "halogen" refers to elements of Group NH or the periodic table, e.g. F, Cl, Br or I.
[00076] An "aryl" group refers to an aromatic group having at least one carbocycUc aromatic group or heterocycUc aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen (e.g. F, Cl, Br, I), haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, diaUcylamino, carboxy or thio or thioa cyl. Νonlimiting examples of aryl rings are phenyl, naphτhyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, fhiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.
[00077] A "hydroxyl" group refers to an OH group. An "alkenyl" group refers to a group having at least one carbon to carbon double bond.
[00078] An "arylalkyl" group refers to an alkyl bound to an aryl, wherein aUcyl and aryl are as defined above. An example of an araUcyl group is a benzyl group.
[00079] As contemplated herein, the present invention relates to the use of a SARM compound and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, Ν-oxide, prodrug, polymorph or crystal or combinations thereof. In one embodiment, the invention relates to the use of an analog of the SARM compound. In another embodiment, the invention relates to the use of a derivative of the SARM compound. In another embodiment, the invention relates to the use of an isomer of the SARM compound. In another embodiment, the invention relates to the use of a metabolite of the SARM compound. In another embodiment, the invention relates to the use of a pharmaceuticaUy acceptable salt of the SARM compound, hi another embodiment, the invention relates to the use of a pharmaceutical product of the SARM compound. In another embodiment, the invention relates to the use of a hydrate of the SARM compound. In another embodiment, the invention relates to the use of an N-oxide of the SARM compound. In another embodiment, the invention relates to the use of aprodrug of the SARM compound. In another embodiment, the invention relates to the use of a polymorph of the SARM compound. In another embodiment, the invention relates to the use of a crystal of the SARM compound. In another embodiment, the invention relates to the use of any of a combination of an analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, or N- oxide, prodrug, polymorph or crystal of the SARM compounds of the present invention.
[00080] As defined herein, the term "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.
[00081] In one embodiment, this invention encompasses the use of various optical isomers of the SARM compounds. It will be appreciated by those skilled in the art that the SARM compounds of the present invention contain at least one chiral center. Accordingly, the SARM compounds used in the methods of the present invention may exist in, and be isolated in, optically-active or racemic forms. Some compounds may also exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereroisomeric form, or mixtures thereof, which form possesses properties useful in the treatment of obesity and related disorders as described herein. In one embodiment, the SARM compounds are the pure (R)-isomers. In another embodiment, the SARM compounds are the pure (S)-isomers. In another embodiment, the SARM compounds are a mixture of the (R) and the (S) isomers. In another embodiment, the SARM compounds are a racemic rnixture comprising an equal amount of the (R) and the (S) isomers. It is weU known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystaUization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
[00082] The invention includes pharmaceuticaUy acceptable salts of amino-substituted compounds with organic and inorganic acids, for example, citric acid and hydrochloric acid. The invention also includes N-oxides of the amino substituents of the compounds described herein. PharmaceuticaUy acceptable salts can also be prepared from the phenolic compounds by treatment with inorganic bases, for example, sodium hydroxide. Also, esters of the phenoUc compounds can be made with aUphatic and aromatic carboxyUc acids, for example, acetic acid and benzoic acid esters.
[00083] This invention further includes derivatives of the SARM compounds. The term "derivatives" includes but is not limited to ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like. In addition, this invention further includes hydrates of the SARM compounds. The term "hydrate" includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like.
[00084] This invention further includes pharmaceutical products of the SARM compounds. The term "pharmaceutical product" means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.
[00085] This invention further includes prodrugs of the SARM compounds. The term "prodrug" means a substance which can be converted in-vivo into a biologically active agent by such reactions as hydrolysis, esterification, desterification, activation, salt formation and the Uke. [00086] This invention further includes crystals of the SARM compounds. Furthermore, this invention provides polymorphs of the SARM compounds. The term "crystal" means a substance in a crystalline state. The term "polymorph" refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.
BIOLOGICAL ACTIVITY OF SELECTIVE ANDROGEN RECEPTOR MODULATOR COMPOUNDS
[00087] Selective androgen receptor modulator (SARM) compounds are a novel class of androgen receptor targeting agents ("ARTA"), that have previously been shown to be useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased Ubido, sexual dysfunction, erectUe dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual Ubido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia„hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and or prevention of acute and/or chroniQ muscular wasting conditions; e) preventing ' ' ' ! , . and/or treating dry eye conditions; f) oral androgen replacement therapy; g) decreasing the incidence of, halting or causing a regression of prostate cancer; and/or h) inducing apoptosis in a cancer ceU.
[00088] As demonstrated herein, it has surprisingly been discovered that SARM compounds are also useful for a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing or faciUtating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity-associated metaboUc disorder, for example hypertension, osteoarthritis, Type H diabetes meUitus, increased bloodpressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting or reducing adipogenesis; i) altering stem cell differentiation; and/or j) altering the level of leptin; comprising administering a therapeutically effective amount of a selective androgen receptor modulator and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, as described herein.
[00089] As demonstrated herein, the SARM compounds of the present invention alter the levels of leptin in a subj ect. In another embodiment, the SARM compounds decrease the levels of leptin and are therefore inhibitors of leptin. In another embodiment, the SARM compounds of the present invention increase the levels of leptin in a subject. As described above, leptin was shown to have an effect on appetite on weight loss in obese mice, and thus has been implicated in obesity (PeUeymounter et al., 1995, Halaas et al., 1995, Campfield et al., 1995). When leptin was injected into grossly obese mice, which possessed two mutant copies of the ob gene, the mice exhibited a reduced appetite and began to lose weight. In addition, leptin played a role in reducing the animals' food intake and in increasing their energy expenditure. Similarly, when normal mice received leptin, they also ate less than the untreated controls. Moreover, it has been suggested by Campfield et al that leptin acts on central neuronal networks to regulate feeding behavior and energy balance.
[00090] As used herein, the term 'leptin inhibitor' refers to a SARM compound which decreases the level of leptin, so that the level of leptin after treatment with the SARM compound is lower than the level of leptin in the absence of the compoimd. As used herein 'increasing the level of leptin' means that the levels of leptin after treatment with the SARM compound is higher than the level of leptin in the absence of the SARM compound. In one embodiment, the term 'level of leptin' refers to the serum level of leptin. As contemplated herein, the SARM compounds of the present invention have an effect on leptin in-vitro and in-vivo. Leptin levels can be measured by methods known to one skilled in the art, for example by commercially available ELISA kits. In addition, Leptin levels may be determined in in-vitro assays, or in in-vivo assays, by any method known to a person skilled in the art.
[00091] Since leptin is impUcated in controlling appetite, weight loss, food intake, and energy expenditure, modulating and/or controUing the levels of leptin is a useful therapeutic approach in treating preventing, inhibiting or reducing the incidence of obesity in subjects suffering from obesity. Modulating the level of leptin can result in a loss of appetite, a reduction of food intake, and an increase in energy expenditure in the subject, and thus may contribute to the control and treatment of obesity.
[00092] The term "obesity" is defined as an increase in body weight beyond the limitation of skeletal and physical requirement, as the result of excessive accumulation of fat in the body.
[00093] The term "obesity-associated metaboUc disorder" means a disorder which results from, is a consequence of, is exacerbated by or is secondary to obesity. Non-limiting examples of such a disorder are osteoarthritis, Type H diabetes meUitus, increased blood pressure, stroke, and heart disease.
[00094] The term "osteoarthritis" refers to a non-inflammatory degenerative joint disease occurring chiefly in older people, characterized by degeneration of the articular cartilage, hypertrophy of bones and the margins and changes in the synovia! membrane. It is accompanied by pain and stiffness, particularly after prolonged activity.
[00095] The term "diabetes" means a relative or absolute lack of insulin leading to uncontrolled carbohydrate metabolism. Most patients can be clinically classified as having either insulin-dependent diabetes mellitus (IDDM or Type-I diabetes) or non- insulin-dependent diabetes meUitus (NIDDM or Type-H diabetes). [00096] The term "increased blood pressure" or "hypertension" refers to a repeatedly high blood pressure above 140 over 90 mmHg. Chronically high blood pressure can cause blood vessel changes in the back of the eye, thickening of the heart muscle, kidney f-rilure, and brain damage.
[00097] The term "stroke" refers to damage to nerve cells in the brain due to insufficient blood supply often caused by a bursting blood vessel or a blood clot. The term "heart disease" refers to a malfunction in the heart normal function and activity, including heart failure.
[00098] In addition, androgens have recently been shown to be involved in commitment of mesenchymal pluripotent cells into myogenic lineage and to block differentiation into adipogenic lineage (Singh et al., Endocrinology, 2003, Jul 24). Accordingly, selective androgen receptor modulator compounds can be useful in methods of blocking adipogenesis, and/or altering stem cell differentiation, as described herein.
[00099] The term "adipogenesis", also referred to as "lipogenesis", refers to the production of fat, either fatty degeneration or fatty infiltration, and also covers the normal deposition of fat or the conversion of carbohydrate or protein to fat.
[000100] The term "stem ceU" refers to a cell that gives rise to a lineage of cells. In the process of stem cells differentiation, these ceUs divide to produce dissimilar daughter ceUs, one replacing the original stem cell, the other differentiating further to different lineages of cells.
[000101 ] As contemplated herein, the SARMs which are useful in preventing and treating obesity are classified as androgen receptor agonists (AR agonists) or androgen receptor antagonists (AR antagonists). [000102] The AR is a ligand-activated transcriptional regulatory protein that mediates induction of male sexual development and function through its activity with endogenous androgens (male sex hormones). The androgenic hormones are steroids which are produced in the body by the testis and the cortex of the adrenal gland. Androgenic steroids play an important role in many physiologic processes, including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth, spermatogenesis, and the male hair pattern (Matsumoto, Endocrinol. Met. Clin. N. Am.23:857-75 (1994)). The endogenous steroidal androgens include testosterone and dihydrotestosterone ("DHT"). Other steroidal androgens include esters of testosterone, such as the cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, and decanoate esters, and other synthetic androgens such as 7-Methyl- Nortestosterone ("MENT") and its acetate ester (Sundaram et al., "7 Alpha-Methyl- Nortestosterone(MENT): The Optimal Androgen For Male Contraception," Ann. Med., 25:199-205 (1993) ("Sundaram")).
[000103] A receptor agonist is a substance which binds receptors and activates them. A receptor antagonist is a substance which binds receptors and inactivates them. In one embodiment, the SARMs which are useful in treating and preventing obesity and which modulate leptin levels are AR agonists, and are, therefore, useful in binding to and activating the AR. In another embodiment, the SARMs which are useful in treating and preventing obesity and which modulate leptin levels are AR antagonists, and are, therefore, useful in binding to and inactivating the AR. Assays to determine whether the compounds of the present invention are AR agonists or antagonists are well known to a person skilled in the art. For example, AR agonistic activity can be determined by monitoring the ability of the SARM compounds to maintain and/or stimulate the growth of AR containing tissue such as prostate and seminal vesicles, as measured by weight. AR antagonistic activity can be determined by monitoring the ability of the SARM compounds inhibit the growth of AR containing tissue. [000104] hi yet another embodiment, the SARM compounds of the present invention can be classified as partial AR agonist/antagonists. The SARMs are AR agonists in some tissues, to cause increased transcription of AR-responsive genes (e.g. muscle anabolic effect). In other tissues, these compounds serve as competitive inhibitors of testosterone/DHT on the AR to prevent agonistic effects of the native androgens.
[000105] The compounds of the present invention bind either reversibly or irreversibly to the androgen receptor. In one embodiment, the SARM compounds bind reversibly to the androgen receptor. In another embodiment, the SARM compounds bind irreversibly to the androgen receptor. The compounds of the present invention may contain a functional group (affinity label) that allows aU ylation of the androgen receptor (i.e. covalent bond formation). Thus, in this case, the compounds bind irreversibly to the receptor and, accordingly, cannot be displaced by a steroid, such as the endogenous ligands DHT and testosterone.
[000106] As defined herein, "contacting" means that the SARM compound of the present mvention is introduced into a sample containing the protein or enzyme in a test tube, flask, tissue culture, chip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit binding of the SARM to the enzyme. Methods for contacting the samples with the SARM or other specific binding components are known to those skilled in the art and may be selected depending on the type of assay protocol to be run. Incubation methods are also standard and are known to those skilled in the art.
PHARMACEUTICAL COMPOSITIONS
[000107] The treatment methods of the present invention comprise, in one embodiment, administering a pharmaceutical preparation comprising the SARM compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymoi h, crystal or any combination thereof; and a pharmaceutically acceptable carrier. [000108] As used herein, "pharmaceutical composition" means a composition comprising an "effective amount" of the active ingredient, i.e. the SARM compound, together with a pharmaceutically acceptable carrier or diluent.
[000109] An "effective amount" as used herein refers to that amount which provides a therapeutic effect for a given condition and administration regimen. An "effective amount" of the SARM compounds as used herein can be in the range of 1-500 mg/day. In one embodiment the dosage is in the range of 1 -100 mg/day. In another embodiment the dosage is in the range of 100-500 mg/day. In another embodiment the dosage is in a range of 45-60 mg/day. In another embodiment the dosage is in the range of 15-25 mg/day. In another embodiment the dosage is in the range of 55-65 mg/day. In another embodiment the dosage is in the range of 45-60 mg/day. The SARM compounds can be administered daily, in single dosage forms containing the entire amount of daily dose, or can be administered daily in multiple doses such as twice daily or three times daUy. The SARM compounds can also be administered mtermittently, for example every other day, 3 days a week, four days a week, five days a week and the like.
[000110] As used herein, the term "treating" includes preventative as weU as disorder remitative treatment. As used herein, the terms "reducing", "suppressing" and "inhibiting" have their commonly understood meaning of lessening or decreasing. As used herein, the term "facilitating" is giving its commonly understood meaning of increasing the rate. As used herein, the term "promoting" is given its commonly understood meaning of increasing. As used herein, the term "progression" means increasing in scope or severity, advancing, growing or becoming worse.
[000111] As used herein, the term "administering" refers to bringing a subject in contact with a SARM compound of the present invention. As used herein, administration can be accomplished in vitro, i.e. in a test tube, or in vivo, i.e. in ceUs or tissues of living organisms, for example humans. In one embodiment, the present mvention encompasses administering the compounds of the present invention to a subject. In one embodiment, the subject is a mammalian subject. In another embodiment, the subject is a human.
[0001 2] The pharmaceutical compositions containing the SARM agent can be administered to a subject by any method known to a person sldUed in the art, such as parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermaUy, subcutaneously, intraperitonealy, intraventricularly, intracranially, intravaginally or intratumoraUy.
[000113] In one embodiment, the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e. as a soUd or a Uquid preparation. Suitable solid oral formulations include tablets, capsules, pUls, granules, pellets and the like. Suitable Uquid oral formulations include solutions, suspensions, dispersions, emulstions, oils and the like. In one embodiment of the present invention, the SARM compounds are formulated in a capsule. In accordance with this embodiment, the compositions of the present invention comprise in addition to the SARM active compound and the inert carrier or dUuent, a hard gelating capsule.
[000114] Further, in another embodiment, the pharmaceutical compositions are at ninistered by intravenous, intraarterial, or intramuscular injection of a Uquid preparation. Suitable liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the tike. In one embodiment, the pharmaceutical compositions are administered intravenously, and are thus formulated in a form suitable for intravenous administration. In another embodiment, the pharmaceutical compositions are administered intraarterially, and are thus formulated in a form suitable for intraarterial administration. In another embodiment, the pharmaceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for intramuscular adininistration. [000115] Further, in another embodiment, the pharmaceutical compositions are aώninistered topicaUy to body surfaces, and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops and the like. For topical administration, the SARM agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the tike are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.
[000116] Further, in another embodiment, the pharmaceutical compositions are administered as a suppository, for example a rectal suppository or a urethral suppository.
Further, in another embodiment, the pharmaceutical compositions are administered by subcutaneous implantation of a pellet. In a further embodiment, the peUet provides for controlled release of SARM agent over a period of time.
[000117] In another embodiment, the active compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid).
[000118] As used herein "pharmaceuticaUy acceptable carriers or diluents" are well known to those skilled in the art. The carrier or dUuent may be a soUd carrier or diluent for solid formuations, a liquid carrier or diluent for Uquid formulations, or mixtures thereof.
[000119] Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof. [000120] For liquid formulations, pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, emulsions or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcohoUc/aqueous solutions, emulsions or suspensions, including saline and buffered media. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil.
[000121] Parenteral vehicles (for subcutaneous, intravenous, intraarterial, or intramuscular injection) include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the tike. Examples are sterile liquids such as water and oUs, with or without the addition of a surfactant and other pharmaceuticaUy acceptable adjuvants. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred Uquid carriers, particularly for injectable solutions. Examples of oUs are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oU, mineral oil, olive oU, sunflower oil, and fish-liver oU.
[000122] hi addition, the compositions may further comprise binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl ceUulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCI, acetate, phosphate) of various pH and ionic strength, additives such as albumin, or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl ceUulose, hyroxypropyhnethyl cellulose), viscosity increasing agents(e.g. carbomer, colloidal siUcon dioxide, ethyl ceUulose, guar gum), sweetners (e.g. aspartame, citric acid), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. coUoidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifϊers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxarnines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.
[000123] In one embodiment, the pharmaceutical compositions provided herein are controlled release compositions, i.e. compositions in which the SARM compound is released over a period of time after administration. Controlled or sustained release compositions include formulation in UpophiUc depots (e.g. fatty acids, waxes, oUs). In another embodiment, the composition is an immediate release composition, i.e. a composition in which all of the SARM compoimd is released immediately after administration.
[000124] In yet another embodiment, the pharmaceutical composition can be delivered in a controlled release system. For example, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, Uposomes, or other modes of administration. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Bio ed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical AppUcations of Controlled
Release, supra, vol.2, pp. 115-138 (1984). Other controUed release systems are discussed in the review by Langer (Science 249:1527-1533 (1990).
[000125] The compositions may also include incorporation of the active material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycohc acid, hydrogels, etc, or onto Uposomes, microemulsions, miceUes, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.) Such compositions will influence the physical state, solubiUty, stability, rate of in vivo release, and rate of in vivo clearance.
[000126] Also comprehended by the mvention are particulate compositions coated with polymers (e.g. poloxamers or poloxamines) and the compound coupled to antibodies directed against tissue-specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors.
[000127] Also comprehended by the invention are compounds modified by the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl ceUulose, dextran, polyvinyl alcohol, polyvinylpyrroUdone or polyproline. The modified compounds are known to exhibit substantiaUy longer half-lives in blood foUowing intravenous inj ection than do the corresponding unmodified compounds (Abuchowski et al., 1981 ; Newmark et al, 1982; and Katre et al., 1987). Such modifications may also increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stabUity of the compound, and greatly reduce the immunogenicity and reactivity of the compound. As a result, the desired in vivo biological activity may be achieved by the administration of such polymer-compound abducts less frequently or in lower doses than with the unmodified compound.
[000128] The preparation of pharmaceutical compositions which contain an active component is well understood in the art, for example by mixing, granulating, or tablet- forming processes. The active therapeutic ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. For oral administration, the SARM agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the tike are mixed with additives customary for this purpose, such as veliicles, stabilizers, or inert dUuents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oUy solutions. For parenteral administration, the SARM agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are converted hito a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other.
[000129] An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms. PharmaceuticaUy acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule), which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
[000130] For use in medicine, the salts of the SARM wiU be pharmaceuticaUy acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
[000131 ] In one embodiment, the methods of the present invention comprise aαniimstering a SARM compound as the sole active ingredient. However, also encompassed within the scope of the present invention are methods or treating obesity as disclosed herein, which comprise adixiinistering the SARM compounds in combination with one or more therapeutic agents. These agents include, hut are not limited to: LHRH analogs, reversible antiandrogens, antiestrogens, anticancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, or agents acting through other nuclear hormone receptors.
[000132] Thus, in one embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an LHRH analog. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with a reversible antiandiO en. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an antiestrogen. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an anticancer drug. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with a 5-alpha reductase inhibitor. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an aromatase inhibitor. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with a progestin. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in' combination with an agent acting through other nuclear hormone receptors.
[000133] The following examples are presented in order to more fully iUustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention. EXPERIMENTAL DETAILS SECTION
EXAMPLE 1; Effect of Compound VI and Compound VH on Organ Weights and Leptin
Levels
VI VH
[000134] In recent pharmacological studies Applicants identified two SARMs (Compounds NI and NH) with high in vitro androgen receptor (AR) binding affinity and in vivo androgenic and anabolic activity. Since Compounds VI and VH show tissue-selective anabohc activity, these compounds were tested for their effects target organ weights and on levels of leptin, a fat biomarker that serves as a marker for anabolic effects and that has been implicated in obesity, in intact male rats after short-term and long-term drug treatment.
Methods:
[000135] Immature male Sprague-Dawleyrats (195-205 gram body weight) were used for this study. Animals were divided into groups of 15 animals (5 animals per time point) to receive one of the following treatments: (1) vehicle control, (2) testosterone propionate dissolved m vehicle solution at a dose of 500 μg/day, (3) Compound VI at dose of 500 μg/day dissolved in vehicle solution, or (4) Compound VH at dose of 500 μg/day dissolved in vehicle solution. All doses were delivered by subcutaneous placement of Alzet osmotic pumps. DaUy food intake was recorded for one-week and two-week studies. [000136] Seven, 14 and 28 days after pump implantation, animals were exsanguinated under ketamine/xylazine anesthesia. Serum was coUected, separated into 10 aUquots and stored at -80°C. Major organs were coUected, weighed and stored at -80°C.
[000137] Serum concentrations of testosterone (T), leptin, Insulin and IGF-1 were determined by commercially available ELISA kits. Serum concentration of Compound VI and Compoimd VH were determined by HPLC.
Results: [000138] The results of the Leptin experiments are shown in Table 1. Compared with the vehicle control, Compound VH decreased serum leptin levels by 36% (2w) and 22% (4w).
[000139] The observed changes in organ weight were consistent with previous studies by Applicants and confirmed the tissue-selective anabolic activity of Compound VI and
Compound VH. Compound VH had a more profound effect on serum leptin concentrations, suggesting it may affect animal body composition and other endocrine systems, such as the hypoτhalamo-pituitary-IGF-1 axis and the reproductive axis.
Table 1:
Compound Compound
Control TP VI vπ P Value(
1.87 ± 0.27 1.74 ± 0.53 1.71± 0.31 1.45 ± 0.47
Leptin lw (100%) (102%) (96%) (84%)
2.62 ± 0.24 2.19 ± 0.67 2.81 ± 0.29 1.68 ± 0.29 **
(ng/ml) 2 (100%) (84%) (107%) (64%) 0.001
6.37 ± 5.89 ± 6.62 ± 1.12 4.89 ±
4 1.31(100%) 0.77(92%) (104%) 0.61(77%) 0.0696
Compound Compound
Control TP vi vπ P Value
Normalized 7.18 ± 1.23 6.67 ± 1.96 6.65 ± 1.07 5.80 ± 1.73 Leptin lw (100%) (93%) (93%) (81%) 0.184
(jpg/ml)/B 2w 8.64 ± 0.81 7.04 ± 1.97 8.99 ± 0.99 5.47 ± 1.03 ** 0.000635 (g) (100%) (92%) (104%) (63%)
17.8 ± 3.3 16.0 ± 1.7 18.7 ±4.2 13.82 ±
4w (100%) (90%) (105%) 1.17**(78%) 0.0359
EXAMPLE 2:
Effect of Compound VI on Lean Body Mass and Percent Body Fat
Methods:
[000140] Two hundred and thirty (230) female Sprague-Dawley rats (23 weeks of age) were used in these studies.
[000141] Animals were randomized (n=10 per group) into each of the treatment groups outlined in Table 2 below. Animals assigned to groups 6 through 23 were ovariectomized on day 0 of the experiment.
[000142] Drug administration with Compound VI, bicalutamide (an antiandrogen), and/or DHT commenced on day 0 or 90 with the compound of interest administered via daily subcutaneous injection (0.20 mL) and continued until day 120 or 210 of the study. Drug solutions were prepared daily by dissolving in DMSO and dilution with PEG 300. The percentage of DMSO was the same in aU vehicles (17.6%), as determined based on the solubility of the test compounds.
[000143] Whole body DEXA images were coUected up to 120 or 210 days after ovariectomy, as described in Table 2. Lean body mass (LBM), fat mass (FM) and total body mass (TBM) were determined at each time point.
[000144] All animals were sacrificed on day 120 or 210. Femurs, tihias, and lumbar vertebrae were excised from the sacrificed rats for future studies. Left femurs, left tibias, and L2-L4 vertebrae were placed in 10% Formalin for 2 days foUowing excision and then moved to 70% Alcohol and stored at 4°C until histomorphometric analysis. Right femurs, right tibias, and L5-L6 vertebrae were stored at in saline soaked gauze at -20°C until mechanical testing. Additionally, right femurs, right tibias, and the vertebral column were scanned by DEXA immediately following excision.
[000145] Nine and two days prior to sacrifice, animals were administered an i.p. injection of Calcein (10 mg/kg).
Table 2:
Results:
[000 46] The effect of Compound VI on lean body mass is shown in Figure 1. Figure 1 A shows the percent change in lean body mass. Figure IB shows the absolute values of lean body mass (in grams). The high dose (3 mg/day) of Compound Nl-t eated group showed 9% increase in lean mass (Figure 1 A), as compared to the ovariectomized (OVX) control group at the 90 day time point. Similar trends were observed for aU dose groups.
[000147] Dose-dependent changes in percent body fat were also observed at the 90 day time point, and are shown in Figure 2. The high dose (3 mg/day) of Compound Vl-treated group showed a 3.6% decrease in body fat as compared to the ovariectomized (OVX) control group. Similar trends were observed for all dose groups. Figure 3 shows the effect of Compound VI on body weight
[0001 8] It will be appreciated by a person sktiled in the art that the present invention is not limited by what has been particularly shown and described hereinabove. Rather, the scope of the invention is defined by the claims which foUow:

Claims

WHAT IS CLAIMED IS;
1. A method of treating obesity a subject suffering from obesity, comprising the step of administering to the subject a selective androgen receptor modulator (SARM), in an amount effective to treat obesity in said subject.
2. The method according to claim 1, comprising administering an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of said SARM compound, or any combination thereof. 3. The method according to claim 1 , wherein said S RM compound is represented by the structure of formula I:
I wherein G is O or S; X is a bond, O, CH2, NH, Se, PR, NO or NR;
T is OH, OR, -NHCOCH3, or NHCOR Z is NO2, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR,
OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is alkyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.
The method according to claim 1, wherein said SARM compound is represented by the structure of formula π.
π wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCHj, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHS02R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
The method according to claim 1 , wherein said SARM compound is represented by the structure of formula EL
m wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
Ri is CH3, CH2F,CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; A is a ring selected from:
B is a ring selected from:
wherem A and B cannot simultaneously be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN CR3 or SnR3;
Qi and Q2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
Q3 and Q are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; i is O, NH, NR, NO or S; and
W2 is N or NO.
The method according to claim 1, wherein said SARM compound is represented by the structure of formula TV:
IV wherem X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
T is OH, OR, -NHCOCH5, or NHCOR;
R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2 or SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3;F, Br, Cl, I, CN, or SnR3;
Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR,NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and m is an integer of 1-3.
7. The method according to claim 1 , wherein said SARM compound is represented by the structure of formula V:
V wherein
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3,
NHCOCF3, NHCOR, aUcyl, arylaUcyl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3,
S11R3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3> F, Br, Cl, I, CN, or SnR3; Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R,
SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
B
n is an integer of 1-4; and m is an integer of 1-3.
8. The method according to claim 1 , wherein said SARM compound is represented by the structure of formula VI. VI
The method according to claim 1, wherein said SARM compound is represented by the structure of formula VH.
Nπ
10. The method according to claim 1, comprising administering a pharmaceutical preparation comprising said SARM and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate,
Ν-oxide, prodrug, polymorph, crystal or any combination thereof; and a pharmaceutically acceptable carrier.
11. A method of preventing, suppressing, inhibiting or reducing the incidence of obesity in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM), in an amount effective to prevent, suppress, inhibit or reduce the incidence of obesity in said subject.
12. The method according to claim 11, comprising administering an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, Ν-oxide, crystal, polymorph or prodrug of said SARM compound, or any combination thereof.
13. The method according to claim 11, wherein said SARM compound is represented by the structure of formula I:
I wherein G is O or S;
X is a bond, O, CH2, NH, Se, PR, NO or NR;
T is OH, OR, -NHCOCH3, or NHCOR
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
A B
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
Rj is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.
The method according to claim 11, wherein said SARM compound is represented by the structure of formula II. π wherein X is a bond, Q, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
A B
R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
15. The method according to claim 11, wherein said SARM compound is represented by the structure of formula HI.
m wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; A is a ring selected from:
B is a ring selected from:
wherein A and B cannot simultaneously be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN CR3 or SnR3;
Qi and Q2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3,
NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR,
CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R,
OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
Q3 and Q are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; i is O, NH, NR, NO or S; and
W2 is N or NO.
16. The method according to claim 11, wherein said SARM compound is represented by the structure of formula IV:
rv wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
T is OH, OR, -NHCOCH3, or NHCOR;
R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, aUcyl, arylaUcyl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, S11R3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO2, CN, COR, COOH, or CONHR; . Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3,NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fusedring system represented by structure A, B or C:
B
n is an integer of 1-4; and m is an integer of 1 -3.
17. The method according to claim 11, wherein said SARM compound is represented by the structure of formula V:
V wherein
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, aUcyl, arylaUcyl, OR, NH2, NHR, NR2 or SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR.3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is alkyl, haloaUcyl, dihaloaUcyl, tiihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
A B
n is an integer of 1-4; and m is an integer of 1-3.
18. The method according to claim 11, wherein said SARM compound is represented by the structure of formula VI.
004
VI
19. The method according to claim 11, wherein said SARM compound is represented by the structure of formula VH.
vπ
20. The method according to claim 11 , comprising administering a pharmaceutical preparation comprising said SARM and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof; and a pharmaceuticaUy acceptable carrier.
21. A method of promoting, increasing or facilitating weight loss in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM), in an amount effective to promote, increase or facilitate weight loss in said subject.
22. The method according to claim 21, comprising administering an analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of said SARM compound, or any combination thereof.
23. The method according to claim 21, wherein said SARM compound is represented by the structure of formula I: 78
I wherein G is O or S;
X is a bond, O, CH2, NH, Se, PR, NO or NR;
T is OH, OR, -NHCOCH3, or NHCOR
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
R! is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.
The method according to claim 21, wherein said SARM compound is represented by the structure of formula II. π wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q togetiαer with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
A B
R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
25. The method according to claim 21, wherein said SARM compound is represented by the structure of fonnula HI.
m wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCBs, or NHCOR; R is aUcyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; A is a ring selected from:
B is a ring selected from:
where n A and B cannot simultaneously be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN CR3 or SnR3;
Qi and Q2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3,
NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR,
CONHR, NHCSCH3, NHCSCF3; NHCSR NHSO2CH3, NHSO2R,
OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
Q3 and Q4 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
Wi is O, NH, NR, NO or S; and
W2 is N or NO.
26. The method according to claim 21, wherein said SARM compound is represented by the structure of formula IV:
IV wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
T is OH, OR, -NHCOCH3, or NHCOR;
Ris aUcyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylaUcyl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure: 04 0
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3j F, Br, Cl, I, CN, or SnR3;
Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCHs, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
B
n is an integer of 1-4; and m is an integer of 1-3.
27. The method according to claim 21, wherein said SARM compound is represented by the structure of formula V:
v wherein
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylaUcyl, OR, NH2, NHR, NR2 or SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F,
CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2,
NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR,
OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR
NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R,
SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
A B
n is an integer of 1-4; and m is an integer of 1-3.
28. The method according to claim 21, wherein said SARM compound is represented by the structure of formula VI.
004/034978
VI
29. The method according to claim 21, wherein said SARM compound is represented by the structure of formula VII.
vπ
30. The method according to claim 21, comprising administering a pharmaceutical preparation comprising said SARM and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof; and a pharmaceutically acceptable carrier.
31. A method of suppressing, inhibiting or reducing appetite of a subject, comprising the step of administering to the subj ect a selective androgen receptor modulator (SARM), in an amount effective to suppress, inhibit or reduce the appetite of said subject.
32. The method according to claim 31, comprising adnrinistering an analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of said SARM compound, or any combination thereof.
33. The method according to claim 31, wherein said SARM compound is represented by the structure of formula I:
I wherein G is O or S;
X is a bond, O, CH2, NH, Se, PR, NO or NR; T is OH, OR, -NHCOCH3, or NHCOR Z is NO2, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q is aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.
The method according to claim 31, wherein said SARM compoimd is represented by the structure of formula II. π wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
35. The method according to claim 31, wherein said SARM compound is represented by the structure of formula HI.
m wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; A is a ring selected from:
B is a ring sele Acted fromA: i-
wherein A and B cannot simultaneo>usly be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN CR3 or SnR3;
Qi and Q2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCFs, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCKs, NHCSCF3, NHCSRNHS02CH3, NHSO2R,
OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
Q3 and Q4 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCHj, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
Wi is O, NH, NR, NO or S; and
W2 is N or NO.
36. The method according to claim 31, wherein said SARM compound is represented by the structure of formula IV:
IV wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
T is OH, OR, -NHCOCH3, or NHCOR;
R is aUcyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, aUcyl, arylaUcyl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together -with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and m is an integer of 1-33.
37. The method according to claim 31, wherein said SARM compound is represented by the structure of formula V:
V wherein
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, aUcyl, arylaUcyl, OR, NH2, NHR, NR2 or SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together •with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; Z is NO2, CN, COR, COOH, or CONHR; Y is CF3) F, Br, Cl, I, CN, or SnR3; Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH,, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and m is an integer of 1-3.
38. The method according to claim 31, wherein said SARM compound is represented by the structure of formula VI.
VI
39. The method according to claim 31, wherein said SARM compound is represented by the structure of formula VII.
vπ
40. The metiiod according to claim 31, comprising administering a pharmaceutical preparation comprising said SARM and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof; and a pharmaceutically acceptable carrier.
41. A method of altering body composition of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM), in an amount effective to alter the body composition of said subj ect.
42. The method according to claim 41, wherein said altering body composition comprises altering lean body mass, fat free body mass, o a combination thereof.
43. The method according to claim 41, comprising administering an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of said SARM compoimd, or any combination thereof. 44. The method according to claim 41, wherein said SARM compound is represented by the structure of formula I:
I wherein G is O or S;
X is a bond, O, CH2, NH, Se, PR, NO or NR;
T is OH, OR, -NHCOCH3, or NHCOR
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
* Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is aUcyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F,
CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.
The method according to claim 41, wherein said SARM compound is represented by the structure of formula II. π wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, S02R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
46. The method according to claim 41, wherein said SARM compoimd is represented by the structure of formula HI.
HI wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; A. is a ring selected from:
wherein A and B cannot simultaneously be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN CR3 or SnR3;
Qi and Q2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCHs, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
Q3 and Q4 are independently of each other a hydrogen, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
Wi is O, NH, NR, NO or S; and
W2 is N or NO. '
The method according to claim 41, wherein said SARM compound is represented by the structure of formula IV:
IV wherein ' X is a bond, O, CH2, NH, Se, PR, NO or NR; G is O or S;
T is OH, OR, -NHCOCH3, or NHCOR; Ris alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F,CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3,
NHCOCF3, NHCOR, aUcyl, arylaUcyl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3,
S11R3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
A B
n is an integer of 1-4; and m is an integer of 1-3.
48. The method according to claim 41, wherein said SARM compound is represented by the structure of formula V:
V wherein
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylaUcyl, OR, NH2, NHR, NR2 or SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; Z is NO2, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3; Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
B
n is an integer of 1-4; and m is an integer of 1-3.
49. The method according to claim 41, wherein said SARM compound is represented by the structure of formula VI.
VI
50. The method according to claim 41, wherein said SARM compound is represented by the structure of formula NH.
VR
51. The method according to claim 41, comprising administering a pharmaceutical preparation comprising said SARM and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof; and a pharmaceutically acceptable carrier.
52. A method of converting fat to lean muscle in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) compound, in an amount effective to convert fat to lean muscle in said subj ect.
53. The method according to claim 52, comprising administering an analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of said SARM compound, or any combination thereof. 54. The method according to claim 52, wherein said SARM compound is represented by the structure of formula I:
I wherein G is O or S;
X is a bond, O, CH2, NH, Se, PR, NO or NR; T is OH, OR, -NHCOCH3, or NHCOR
Z is NO2, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR
NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F,
CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.
The method according to claim 52, wherein said SARM compound is represented by the structure of formula II. π wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
56. The method according to claim 52, wherein said SARM compound is represented by the structure of formula HI. '
m wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCHj, or NHCOR; R is alkyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF ':2. CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; A is a ring selected from:
B is a ring selected from:
wherein A and B cannot simultaneously, be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN CR3 or SnR3;
Qi and Q2 are independently of each other a hydrogen, ahcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3s NHCSRNHSO2CH3, NHSO2R,
OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
Qj and Q are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3. NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
Wi is O, NH, NR, NO or S; and
W2 is N or NO.
The method according to claim 52, wherein said SARM compound is represented by the structure of formula IN:
IN wherein X is a bond, O, CH2, ΝH, Se, PR, NO or NR;
G is O or S;
T is OH, OR, -NHCOCH3, or NHCOR;
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
Ri is CHj, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR,NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
B
n is an integer of 1-4; and m is an integer of 1-3.
58. The method according to claim 52, wherein said SARM compound is represented by the structure of formula V:
V wherein
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylaUcyl, OR, NH2,NHR, NR2 or SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; Z is NO2, CN, COR, COOH, or CONHR; Y is CF3,F, Br, Cl, I, CN, or SnR3; Q is H, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
A B
n is an integer of 1-4; and m is an integer of 1-3.
59. The method according to claim 52, wherein said SARM compound is represented by the structure of formula VI.
VI
60. The method according to claim 52, wherein said SARM compound is represented by the structure of formula VII.
vπ
61. The method according to claim 52, comprising administering a pharmaceutical preparation comprising said SARM and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof; and a pharmaceuticaUy acceptable carrier.
62. A method of treating a subject suffering from an obesity-associated metaboUc disorder, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) compound, in an amount effective to treat said obesity-associated metabolic disorder in said subject.
63. The method according to claim 62, wherein the obesity-associated metaboUc disorder is hypertension, osteoarthritis, Type II diabetes meUitus, increased blood pressure, stroke, or heart disease. 64. The method according to claim 62, comprising administering an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of said SARM compound, or any combination thereof.
65. The method according to claim 62, wherein said SARM compound is represented by the structure of formula I:
I wherein G is O or S;
X is a bond, O, CH2, NH, Se, PR, NO or NR;
T is OH, OR, -NHCOCH3, or NHCOR
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2,
NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR,
OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR
NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR,
NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure
A, B or C:
A . B .
R is aUcyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.
66. The method according to claim 62, wherein said SARM compound is represented by the structure of formula H 04/034978
π wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is alkyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
67. The method according to claim 62, wherein said SARM compound is represented by the structure of formula HI.
m wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; A is a ring selected from:
B is a ring selected from:
wherein A and B cannot simultaneously be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN CR3 or SnR3; Qi and Q2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
Q3 and Q4 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; i is O, NH, NR, NO or S; and
W2 is N or NO.
The method according to claim 62, wherein said SARM compound is represented by the structure of formula IV:
IV wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
T is OH, OR, -NHCOCH3, or NHCOR;
R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Ri is-CK-3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, aUcyl, aiyialkyl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, S11R3, or R together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and m is an integer of 1-33.
69. The method according to claim 62, wherein said SARM compound is represented by the structure of formula V:
V wherein
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, aUcyl, arylaUcyl, OR, NH2, NHR, NR2 or SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, S11R3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is alkyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2,
NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR,
OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR
NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R,
SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
B
n is an integer of 1-4; and " m is an integer of 1-3.
70. The method according to claim 62, wherein said SARM compound is represented by the structure of formula VI.
VI
71. The method according to claim 62, wherein said SARM compound is represented by the structure of formula VII.
vπ
72. The method according to claim 62, comprising administering a pharmaceutical preparation comprising said SARM and/or its analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof; and a pharmaceuticaUy acceptable carrier.
73. A method of decreasing, suppressing, inhibiting or reducing adipogenesis in a subject, comprising the step of admini stering to the subject a selective androgen receptor modulator (SARM) compound, in an amount effective to decrease, suppress, inhibit or reduce adipogenesis in said subject.
74. The method according to claim 73, comprising administering an analog, derivative, isomer, metabolite, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of said SARM compound, or any combination thereof.
75. The method according to claim 73, wherein said SARM compound is represented by the structure of formula I:
I wherein G is O or S;
X is a bond, O, CH2, NH, Se, PR, NO or NR; . T is OH, OR, -NHCOCH3, or NHCOR
Z is NO2, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
Ris alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.
76. The method according to claim 73, wherein said SARM compound is represented by the structure of formula II. n wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is aUcyl, F, Cl, Br, I, CF3, CN CR3, ShR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
The method according to claim 73, wherein said SARM compound is represented by the structure of formula HI.
m wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH,, or NHCOR; Ris alkyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; A is a ring selected from:
B is a ring selected from:
w erein A and B cannot simultaneously be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN CR3 or SnR3; Qi and Q2 are independently of each other a hydrogen, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NΗCSRNHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
04/034978
Qj and Q4 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
Wi is O, NH, NR, NO or S; and
W2 is N or NO.
78 . ; The method according to claim 73, wherein said SARM compound is represented by the structure of formula IV:
IV wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
T is OH, OR, -NHCOCHs, or NHCOR;
R is aUcyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, S11R3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
B
n is an integer of 1-4; and m is an integer of 1 -3.
The method according to claim 73, wherein said SARM compound is represented by the structure of formula V:
v wherein
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, aUcyl, arylaUcyl, OR, NH2, NHR, NR2 or SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is alkyl, haloalkyl, dihaloaUcyl, frihaloaUcyl, ,CH2F,
CHF2, CF3, CF2CF3. aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2,
NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR,
OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR
NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R,
SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and m is an integer of 1-3.
The method according to claim 73, wherein said SARM compound is represented by the structure of formula VI.
VI
81. The method according to claim 73, wherein said SARM compound is represented by the structure of formula VII.
82. The method according to claim 73, comprising administering a pharmaceutical preparation comprising said SARM and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof; and a pharmaceutically acceptable carrier.
83. A method of altering stem cell differentiation in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) compound, in an amount effective to alter stem cell differentiation in said subject.
84. The method according to claim 83, comprising adπrinistering an analog, derivative, isomer, metaboUte, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph or prodrug of said SARM compound, or any combination thereof.
85. The method according to claim 83, wherein said SARM compound is represented by the structure of formula I: I wherein G is O or S;
X is a bond, O, CH2, NH, Se, PR, NO or NR; T is OH, OR, -NHCOCHs, or NHCOR Z is NO2, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q is aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCHs, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F,
CHF , CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.
! 6. The method according to claim 83, wherein said SARM compound is represented by the structure of formula H. π wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
A B
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
87. The method according to claim 83, wherein said SARM compoimd is represented by the structure of formula m.
m wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3, or NHCOR; R is aUcyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; A is a ring selected from:
B is a ring sel Aected from:
wherein A and B cannot simultaneously be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN CR3 or SnR3;
Qi and Q2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3,
NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR,
CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R,
OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
Q3 and Q are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
Wi is O, NH, NR, NO or S; and
W2 isN orNO.
88 . The method according to claim 83, wherein said SARM compound is represented by the structure of formula IN: •
IN wherein X is a bond, O, CH2, ΝH, Se, PR, NO or NR;
G is O or S;
T is OH, OR, -NHCOCHj, or NHCOR;
R is aUcyl, haloaUcyl, d aloalkyl,tri-Qaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, aUcyl, arylaUcyl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, S11R3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3,F, Br, Cl, I, CN, or SnR3;
Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR,NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
B
n is an integer of 1-4; and m is an integer of 1-3.
89. The method according to claim 83, wherein said SARM compound is represented by the structure of formula V:
V wherem
R2 is F, Cl, Br, I, CH3, CF3. OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylaUcyl, OR, NH2, NHR, NR2 or SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, S11R3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is alkyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F,
CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH;
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3,F, Br, Cl, I, CN, or SnR3;
Q is H, aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2,
NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR,
OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR
NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R,
SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by
n is an integer of 1-4; and m is an integer of 1-3.
The method according to claim 83, wherein said SARM compound is represented by the structure of formula VI.
VI
91. The method according to claim 83, wherein said SARM compound is represented by the structure of formula NU.
vπ
92. The method according to claim 83, comprising administering a pharmaceutical preparation comprising said SARM and/or its analog, derivative, isomer, metaboUte, pharmaceuticaUy acceptable salt, pharmaceutical product, hydrate, Ν-oxide, prodrug, polymorph, crystal or any combination thereof; and a pharmaceuticaUy acceptable carrier.
93. A method of altering the level of leptin in a subject, said method comprising the step of administering to the subject a selective androgen receptor modulator (SARM), in an amount effective to alter the level of leptin in said subj ect.
94. The method according to claim 93, wherein said altering comprises decreasing, suppressing, inhibiting or reducing the level of leptin in said subject.
95. The method according to claim 93, comprising administering an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, Ν-oxide, crystal, polymorph or prodrug of said SARM compound, or any combination thereof. 96. The method according to claim 93, wherein said SARM compound is represented by the structure of formula I:
I wherein G is O or S;
X is a bond, O, CH2, NH, Se, PR, NO or NR;
T is OH, OR, -NHCOCHs, or NHCOR
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F,- 1, Br, Cl, CN, CR3 or SnR3;
Q is aUcyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCFs, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH; and
Ri is CH3, CH2F,CHF2, CF3, CH2CH3, or CF2CF3.
The method according to claim 93, wherein said SARM compound is represented by the structure of formula II.
E wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;
Q is alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is alkyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, aUcenyl or OH.
The method according to claim 93, wherein said SARM compound is represented by the structure of formula HI.
m wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
G is O or S;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCHs, or NHCOR; R is alkyl, haloalkyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aiyl, phenyl, F, Cl, Br, I, aUcenyl or OH; A is a ring selected from:
B is a ring selected from:
wherein and B cannot simultaneously be a benzene ring; Z is NO2, CN, COOH, COR, NHCOR or CONHR;
Y is CF3, F, I, Br, Cl, CN CR3 or SnR3;
Qi and Q2 are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3,
NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR,
CONHR, NHCSCH3, NHCSCFs, NHCSR NHSO2CH3, NHSO2R,
OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN,
Oj and Q are independently of each other a hydrogen, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
Wi is O, NH, NR, NO or S; and
W2 is N or NO.
99 . The method according to claim 93, wherein said SARM compoimd is represented by the structure of formula IV:
IN wherein X is a bond, O, CH2, ΝH, Se, PR, NO or NR;
Gis O or S;
T is OH, OR, -NHCOCH3, or NHCOR;
Ris aUcyl, haloaUcyl, dihaloaUcyl, trihaloaUcyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
Ri is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, aUcyl, arylaUcyl, OR, NH2, NHR, NR2 or SR;
R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, S11R3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO2, CN, COR, COOH, or CONHR;
Y is CF3, F, Br, Cl, I, CN, or SnR3;
Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR,NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and m is an integer of 1-3.
The method according to claim 93, wherein said SARM compound is represented by the structure of formula V:
v wherein
R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, aUcyl, arylaUcyl, OR, NH2, NHR, NR2 or SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
R is aUcyl, haloalkyl, dihaloaUcyl, trUialoaUcyl, CH2F, CHF2, CF3, CF2CF3, atyl, phenyl, F, Cl, Br, I, aUcenyl or OH; Z is NO2, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3; Q is H, alkyl, F, Cl, Br, I, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, , OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, OCN; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and m is an integer of 1 -3.
1. The method according to claim 93, wherein said SARM compound is represented by the structure of formula VI.
VI
102. The method according to claim 93, wherein said SARM compound is represented by the structure of formula VII.
vπ
103. The method according to claim 93, comprising admimstering a pharmaceutical preparation comprising said SARM and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof; and a pharmaceutically acceptable carrier.
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CN1726019A (en) 2006-01-25
US20040224979A1 (en) 2004-11-11
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